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Natalizumab for Crohn’s Disease: Down but Not Out
EDITORIAL Natalizumab for Crohn’s Disease: Down but Not Out mmunosuppressive therapy with anti–tumor necrosis factor (anti-TNF) agents and immunomodulators has become the primary means of treating moderate to severe Crohn’s disease (CD).1 The superiority of infliximab over azathioprine for the treatment of early CD was shown in the SONIC trial.2 Despite the clear benefit of anti-TNF therapy in CD, a significant proportion of individuals are nonresponders or subsequently lose response.3,4 Loss of response likely is multifactorial, but an important contributor in many cases is antidrug antibody formation, which potentially can be reduced via combination therapy with an immunomodulator.2 However, for primary nonresponders or secondary nonresponders without antibody formation, there may be a significant therapeutic advantage to transitioning to an agent with an alternative mechanism of action.5 Natalizumab was the first biologic drug with an alternative mechanism of action to be approved by the Food and Drug Administration for the treatment of CD. A humanized monoclonal antibody directed against the a4 subunit of integrin heterodimers, this agent inhibits leukocyte adhesion within the vasculature.6 Natalizumab inhibits binding to both a4b7 integrins, located primarily in the vasculature of the gut, and a4b1 integrins, located primarily in the vasculature of the brain.7,8 In initial randomized controlled trials, natalizumab showed efficacy in both multiple sclerosis (MS) and CD.7,9 In the ENACT trial in CD, 56% of individuals receiving natalizumab had a clinical response and 37% achieved remission at 10 weeks; at 60 weeks, 54% of patients with an initial response continued to respond.9 Despite this promising efficacy, it soon was noted during further follow-up evaluation of patients receiving the agent with MS and in clinical trial participants with CD that there was a significant potential complication with this agent that had not been appreciated previously: progressive multifocal leukoencephalopathy (PML). In 2005, there were 3 cases of PML reported, in 2 patients with MS and in 1 patient with CD.10–12 This devastating neurologic condition, comprising lytic demyelination within the central nervous system (CNS), often leads to significant morbidity and mortality, with mortality rates approaching 25%.13 Patients who do survive the disorder often are left with profound permanent neurologic sequelae. PML was exceedingly rare before the human immunodeficiency virus era, and was seen only in patients with profound immunosuppression caused by hematologic malignancies or after organ transplant.14 Rates increased dramatically during the peak of the acquired immune deficiency syndrome epidemic, with up to 5% of individuals with acquired immune deficiency
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Clinical Gastroenterology and Hepatology 2015;13:1926–1928
syndrome developing the disorder. However, the association of this syndrome with a specific immunosuppressive therapy was unique, although it is important to note that all 3 initial cases reported were receiving additional immunosuppressive therapies.10–12 As a result, the use of natalizumab was suspended temporarily in 2005 but resumed 4 months later for MS and in 2008 for CD through a comprehensive patient safety monitoring program, Tysabri Outreach: Unified Commitment to Health.15 The association between PML and reactivation of the John Cunningham virus (JCV) first was described when a polyoma-like virus was isolated in the brain tissue of an individual with PML complicating Hodgkin’s disease.16 JCV antibodies later were discovered in both HIVpositive and HIV-negative individuals with PML.14,17 This human-specific ubiquitous virus often lies dormant in the kidneys, bone marrow, lymphoid tissues, and oligodendrocytes of the CNS in the immunocompetent host.14,18,19 In patients with impaired cellular immunity, however, JCV reactivation leads to the destruction of astrocytes and oligodendrocytes. Focal demyelination results in symptom complexes corresponding with the involved areas within the CNS, ranging from focal neurologic deficits to profoundly impaired cognition. The prevalence of JCV seropositivity in the general population varies widely, with observed rates of 39% to 91%.20 Two large multinational cohorts including a combined 18,000 patients with MS reported strikingly similar JCV seroprevalence rates of 57.1% and 57.6%, with each cohort showing higher rates with increasing age, male sex, and country of origin, but not prior immunosuppression.20,21 Unfortunately, there are limited studies on JCV seroprevalence in CD. Single-center data from Leuven showed JCV seropositivity rates of 76% among 125 patients with CD on immunosuppressive therapy, which was statistically higher than that among 106 healthy volunteers (52%) and numerically higher than that among 99 non–inflammatory bowel disease gastrointestinal controls (65%).22 In this month’s issue of Clinical Gastroenterology and Hepatology, Bellaguarda et al23 presented data examining the prevalence of JCV seropositivity and the clinical impact of natalizumab in refractory CD. Of 191 patients tested, 97% of whom had received prior anti-TNF therapy, JCV seroprevalence was not dissimilar from that in the general or MS population, at 67.5%. After adjusting for age, disease phenotype, C-reactive protein level, and use of corticosteroids and other immunosuppressants, only prior thiopurine use was associated significantly with seropositivity, although there was a suggestion that the use of methotrexate and a lower C-reactive protein level also could be associated with seropositivity. During follow-up evaluation of the 22 patients who were JCV negative and initiated natalizumab, 1 patient became JCV antibody positive
November 2015
after 22 months of therapy. When examining subsequent clinical outcomes, the use of natalizumab was associated with significantly decreased rates of surgery. There are several important considerations when interpreting these results. Although the sample size was relatively small, unlike the large MS cohorts described earlier, if we assume that these data are representative of patients with CD in general, then approximately one third of patients would be JCV antibody negative and therefore appropriate candidates for natalizumab therapy. Among patients who were JCV antibody negative, there has never been a case of PML, and the reported rate of 0.09 or less per 1000 in JCV-negative patients in MS is purely hypothetical.24 Furthermore, seroconversion rates in MS have been shown to be low at 2% to 3%, which makes natalizumab a potentially durable treatment option in patients who respond to the drug. These data should be particularly reassuring to patients and physicians considering natalizumab. For the other two thirds of patients who would be JCV seropositive, natalizumab remains a viable, albeit less appealing, option, especially in patients with severe refractory CD and limited medication options. In MS, the risk of PML is relatively low at 1.6 per 1000 during the first 2 years of natalizumab monotherapy in patients with prior immunosuppressant exposure.24 Extending therapy for an additional 2 years in such patients would yield a risk of 11.1 per 1000, which is still somewhat low and may be entirely acceptable to patients with otherwise medically refractory disease who are deriving benefit from the drug. Of note, whether these risks of PML are similar in patients with CD has not been determined. In the study by Bellaguarda et al,23 22 patients treated with natalizumab were JCV antibody negative and 16 were JCV antibody positive. Interestingly, not only did the use of natalizumab lead to lower rates of surgery, but among patients treated with natalizumab, those who were JCV antibody positive had numerically lower rates of surgery over time than those who were JCV antibody negative. Another point worth considering is that it would be exceedingly unlikely for patients to develop PML during the first 3 months of natalizumab therapy, even if JCV seropositive, and thus patients who do not respond within this time period most likely would discontinue the drug and not incur any risk of PML. The study by Bellaguarda et al23 also reminds us that natalizumab is an effective therapy for some patients with moderate to severe CD. Showing a 77% reduction rate of a hard end point, such as surgery, is clinically important. In a Markov model examining the use of natalizumab and JCV antibody testing, we found that among patients who otherwise would not use natalizumab, testing for JCV antibody and subsequent use of natalizumab after a negative test result could prevent more than 1300 surgeries per 5000 patients in the first year and that, in certain situations, the use of natalizumab was preferable to switching to adalimumab after loss of response to infliximab.25
Editorial 1927
With the advent of the gut-specific anti-integrin, vedolizumab, one may think that the risk of PML with natalizumab does not warrant using this agent. However, it is important to note that although it is challenging to compare response rates from one randomized controlled trial with another, raw response and remission rates seen with natalizumab exceeded those with vedolizumab in CD clinical trials. Although this observation in part may be owing to premature end points in the GEMINI trials, it also is possible that vedolizumab may have reduced efficacy owing to its less systemic mechanism of action. Until this issue is investigated further, it is likely that vedolizumab will be used preferentially over natalizumab in CD. However, such a preference will create another avenue for natalizumab use, namely as a secondline anti-integrin after loss of response to vedolizumab. Given the relatively high rates of loss of response to anti-TNF agents over time, often mediated by the formation of antidrug antibodies, it would be surprising if a similar phenomenon did not occur with vedolizumab because it also is a monoclonal antibody and therefore immunogenic. At the end of the day, we still do not have many effective medical therapies for patients with moderate to severe CD. Although natalizumab received a significant blow after its association with PML, the fight is far from over and this drug still has a potential important role in the treatment of refractory CD. FRANK I. SCOTT, MD, MSCE Division of Gastroenterology Department of Medicine Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania MARK T. OSTERMAN, MD, MSCE Division of Gastroenterology Department of Medicine University of Pennsylvania Philadelphia, Pennsylvania
References 1. Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013; 145:1459–1463. 2. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 3. Osterman MT, Haynes K, Delzell E, et al. Comparative effectiveness of infliximab and adalimumab for Crohn’s disease. Clin Gastroenterol Hepatol 2014;12:811–817. 4. Osterman MT, Haynes K, Delzell E, et al. Effectiveness and safety of immunomodulators with anti-TNF therapy for Crohn’s disease. Clin Gastroenterol Hepatol 2015;13:1293–1301.
1928 Scott and Osterman 5. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:1133–1139. 6. Yednock TA, Cannon C, Fritz LC, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63–66. 7. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.
Clinical Gastroenterology and Hepatology Vol. 13, No. 11 17. Weber F, Goldmann C, Kramer M, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001;49:636–642. 18. Markowitz RB, Thompson HC, Mueller JF, et al. Incidence of BK virus and JC virus viruria in human immunodeficiency virusinfected and -uninfected subjects. J Infect Dis 1993;167:13–20. 19. Kitamura T, Aso Y, Kuniyoshi N, et al. High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. J Infect Dis 1990;161:1128–1133.
8. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32.
20. Bozic C, Subramanyam M, Richman S, et al. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol 2014;21:299–304.
9. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–1925.
21. Olsson T, Achiron A, Alfredsson L, et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Mult Scler 2013;19:1533–1538.
10. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368.
22. Verbeeck J, Van Assche G, Ryding J, et al. JC viral loads in patients with Crohn’s disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy? Gut 2008;57:1393–1397.
11. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353:369–374. 12. Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381. 13. Dong-Si T, Gheuens S, Gangadharan A, et al. Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neurovirol 2015:Epub ahead of print. 14. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9:425–437. 15. Honey K. The comeback kid: TYSABRI now FDA approved for Crohn disease. J Clin Invest 2008;118:825–826. 16. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1:1257–1260.
23. Bellaguarda E, Keyashian K, Pekow J, et al. Prevalence of antibodies against JC virus in patients with refractory Crohn’s disease and effects of natalizumab therapy. Clin Gastroenterol Hepatol 2015;13:1919–1925. 24. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880. 25. Scott FI, Osterman MT, McConnell RA, et al. Impact of JC virus antibody testing in patients with Crohn’s disease with loss of response to infliximab: a Markov model. Inflamm Bowel Dis 2013;19:2625–2633. Conflicts of interest The authors disclose the following: Frank Scott has received research support from Takeda; Mark Osterman is an advisor for Janssen, AbbVie, UCB, Elan, and Takeda, and has received research support from UCB. Most current article http://dx.doi.org/10.1016/j.cgh.2015.07.020
I
Clinical Gastroenterology and Hepatology 2015;13:1926–1928
syndrome developing the disorder. However, the association of this syndrome with a specific immunosuppressive therapy was unique, although it is important to note that all 3 initial cases reported were receiving additional immunosuppressive therapies.10–12 As a result, the use of natalizumab was suspended temporarily in 2005 but resumed 4 months later for MS and in 2008 for CD through a comprehensive patient safety monitoring program, Tysabri Outreach: Unified Commitment to Health.15 The association between PML and reactivation of the John Cunningham virus (JCV) first was described when a polyoma-like virus was isolated in the brain tissue of an individual with PML complicating Hodgkin’s disease.16 JCV antibodies later were discovered in both HIVpositive and HIV-negative individuals with PML.14,17 This human-specific ubiquitous virus often lies dormant in the kidneys, bone marrow, lymphoid tissues, and oligodendrocytes of the CNS in the immunocompetent host.14,18,19 In patients with impaired cellular immunity, however, JCV reactivation leads to the destruction of astrocytes and oligodendrocytes. Focal demyelination results in symptom complexes corresponding with the involved areas within the CNS, ranging from focal neurologic deficits to profoundly impaired cognition. The prevalence of JCV seropositivity in the general population varies widely, with observed rates of 39% to 91%.20 Two large multinational cohorts including a combined 18,000 patients with MS reported strikingly similar JCV seroprevalence rates of 57.1% and 57.6%, with each cohort showing higher rates with increasing age, male sex, and country of origin, but not prior immunosuppression.20,21 Unfortunately, there are limited studies on JCV seroprevalence in CD. Single-center data from Leuven showed JCV seropositivity rates of 76% among 125 patients with CD on immunosuppressive therapy, which was statistically higher than that among 106 healthy volunteers (52%) and numerically higher than that among 99 non–inflammatory bowel disease gastrointestinal controls (65%).22 In this month’s issue of Clinical Gastroenterology and Hepatology, Bellaguarda et al23 presented data examining the prevalence of JCV seropositivity and the clinical impact of natalizumab in refractory CD. Of 191 patients tested, 97% of whom had received prior anti-TNF therapy, JCV seroprevalence was not dissimilar from that in the general or MS population, at 67.5%. After adjusting for age, disease phenotype, C-reactive protein level, and use of corticosteroids and other immunosuppressants, only prior thiopurine use was associated significantly with seropositivity, although there was a suggestion that the use of methotrexate and a lower C-reactive protein level also could be associated with seropositivity. During follow-up evaluation of the 22 patients who were JCV negative and initiated natalizumab, 1 patient became JCV antibody positive
November 2015
after 22 months of therapy. When examining subsequent clinical outcomes, the use of natalizumab was associated with significantly decreased rates of surgery. There are several important considerations when interpreting these results. Although the sample size was relatively small, unlike the large MS cohorts described earlier, if we assume that these data are representative of patients with CD in general, then approximately one third of patients would be JCV antibody negative and therefore appropriate candidates for natalizumab therapy. Among patients who were JCV antibody negative, there has never been a case of PML, and the reported rate of 0.09 or less per 1000 in JCV-negative patients in MS is purely hypothetical.24 Furthermore, seroconversion rates in MS have been shown to be low at 2% to 3%, which makes natalizumab a potentially durable treatment option in patients who respond to the drug. These data should be particularly reassuring to patients and physicians considering natalizumab. For the other two thirds of patients who would be JCV seropositive, natalizumab remains a viable, albeit less appealing, option, especially in patients with severe refractory CD and limited medication options. In MS, the risk of PML is relatively low at 1.6 per 1000 during the first 2 years of natalizumab monotherapy in patients with prior immunosuppressant exposure.24 Extending therapy for an additional 2 years in such patients would yield a risk of 11.1 per 1000, which is still somewhat low and may be entirely acceptable to patients with otherwise medically refractory disease who are deriving benefit from the drug. Of note, whether these risks of PML are similar in patients with CD has not been determined. In the study by Bellaguarda et al,23 22 patients treated with natalizumab were JCV antibody negative and 16 were JCV antibody positive. Interestingly, not only did the use of natalizumab lead to lower rates of surgery, but among patients treated with natalizumab, those who were JCV antibody positive had numerically lower rates of surgery over time than those who were JCV antibody negative. Another point worth considering is that it would be exceedingly unlikely for patients to develop PML during the first 3 months of natalizumab therapy, even if JCV seropositive, and thus patients who do not respond within this time period most likely would discontinue the drug and not incur any risk of PML. The study by Bellaguarda et al23 also reminds us that natalizumab is an effective therapy for some patients with moderate to severe CD. Showing a 77% reduction rate of a hard end point, such as surgery, is clinically important. In a Markov model examining the use of natalizumab and JCV antibody testing, we found that among patients who otherwise would not use natalizumab, testing for JCV antibody and subsequent use of natalizumab after a negative test result could prevent more than 1300 surgeries per 5000 patients in the first year and that, in certain situations, the use of natalizumab was preferable to switching to adalimumab after loss of response to infliximab.25
Editorial 1927
With the advent of the gut-specific anti-integrin, vedolizumab, one may think that the risk of PML with natalizumab does not warrant using this agent. However, it is important to note that although it is challenging to compare response rates from one randomized controlled trial with another, raw response and remission rates seen with natalizumab exceeded those with vedolizumab in CD clinical trials. Although this observation in part may be owing to premature end points in the GEMINI trials, it also is possible that vedolizumab may have reduced efficacy owing to its less systemic mechanism of action. Until this issue is investigated further, it is likely that vedolizumab will be used preferentially over natalizumab in CD. However, such a preference will create another avenue for natalizumab use, namely as a secondline anti-integrin after loss of response to vedolizumab. Given the relatively high rates of loss of response to anti-TNF agents over time, often mediated by the formation of antidrug antibodies, it would be surprising if a similar phenomenon did not occur with vedolizumab because it also is a monoclonal antibody and therefore immunogenic. At the end of the day, we still do not have many effective medical therapies for patients with moderate to severe CD. Although natalizumab received a significant blow after its association with PML, the fight is far from over and this drug still has a potential important role in the treatment of refractory CD. FRANK I. SCOTT, MD, MSCE Division of Gastroenterology Department of Medicine Center for Clinical Epidemiology and Biostatistics Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania MARK T. OSTERMAN, MD, MSCE Division of Gastroenterology Department of Medicine University of Pennsylvania Philadelphia, Pennsylvania
References 1. Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013; 145:1459–1463. 2. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–1395. 3. Osterman MT, Haynes K, Delzell E, et al. Comparative effectiveness of infliximab and adalimumab for Crohn’s disease. Clin Gastroenterol Hepatol 2014;12:811–817. 4. Osterman MT, Haynes K, Delzell E, et al. Effectiveness and safety of immunomodulators with anti-TNF therapy for Crohn’s disease. Clin Gastroenterol Hepatol 2015;13:1293–1301.
1928 Scott and Osterman 5. Afif W, Loftus EV Jr, Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010;105:1133–1139. 6. Yednock TA, Cannon C, Fritz LC, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992;356:63–66. 7. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.
Clinical Gastroenterology and Hepatology Vol. 13, No. 11 17. Weber F, Goldmann C, Kramer M, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001;49:636–642. 18. Markowitz RB, Thompson HC, Mueller JF, et al. Incidence of BK virus and JC virus viruria in human immunodeficiency virusinfected and -uninfected subjects. J Infect Dis 1993;167:13–20. 19. Kitamura T, Aso Y, Kuniyoshi N, et al. High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. J Infect Dis 1990;161:1128–1133.
8. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32.
20. Bozic C, Subramanyam M, Richman S, et al. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol 2014;21:299–304.
9. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912–1925.
21. Olsson T, Achiron A, Alfredsson L, et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Mult Scler 2013;19:1533–1538.
10. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368.
22. Verbeeck J, Van Assche G, Ryding J, et al. JC viral loads in patients with Crohn’s disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy? Gut 2008;57:1393–1397.
11. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353:369–374. 12. Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381. 13. Dong-Si T, Gheuens S, Gangadharan A, et al. Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neurovirol 2015:Epub ahead of print. 14. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9:425–437. 15. Honey K. The comeback kid: TYSABRI now FDA approved for Crohn disease. J Clin Invest 2008;118:825–826. 16. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1:1257–1260.
23. Bellaguarda E, Keyashian K, Pekow J, et al. Prevalence of antibodies against JC virus in patients with refractory Crohn’s disease and effects of natalizumab therapy. Clin Gastroenterol Hepatol 2015;13:1919–1925. 24. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880. 25. Scott FI, Osterman MT, McConnell RA, et al. Impact of JC virus antibody testing in patients with Crohn’s disease with loss of response to infliximab: a Markov model. Inflamm Bowel Dis 2013;19:2625–2633. Conflicts of interest The authors disclose the following: Frank Scott has received research support from Takeda; Mark Osterman is an advisor for Janssen, AbbVie, UCB, Elan, and Takeda, and has received research support from UCB. Most current article http://dx.doi.org/10.1016/j.cgh.2015.07.020