Natalizumab for Crohn’s Disease: Down but Not Out
2015; Elsevier BV; Volume: 13; Issue: 11 Linguagem: Inglês
10.1016/j.cgh.2015.07.020
ISSN1542-7714
AutoresFrank I. Scott, Mark T. Osterman,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoImmunosuppressive 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).1Terdiman J.P. Gruss C.B. Heidelbaugh J.J. 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: 1459-1463Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar The superiority of infliximab over azathioprine for the treatment of early CD was shown in the SONIC trial.2Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2442) Google Scholar Despite the clear benefit of anti-TNF therapy in CD, a significant proportion of individuals are nonresponders or subsequently lose response.3Osterman M.T. Haynes K. Delzell E. et al.Comparative effectiveness of infliximab and adalimumab for Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 811-817Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 4Osterman M.T. Haynes K. Delzell E. et al.Effectiveness and safety of immunomodulators with anti-TNF therapy for Crohn's disease.Clin Gastroenterol Hepatol. 2015; 13: 1293-1301Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar 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.2Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2442) Google Scholar 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.5Afif W. Loftus Jr., E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (429) Google Scholar 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 α4 subunit of integrin heterodimers, this agent inhibits leukocyte adhesion within the vasculature.6Yednock T.A. Cannon C. Fritz L.C. et al.Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin.Nature. 1992; 356: 63-66Crossref PubMed Scopus (1519) Google Scholar Natalizumab inhibits binding to both α4β7 integrins, located primarily in the vasculature of the gut, and α4β1 integrins, located primarily in the vasculature of the brain.7Polman C.H. O'Connor P.W. Havrdova E. et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 899-910Crossref PubMed Scopus (2641) Google Scholar, 8Ghosh S. Goldin E. Gordon F.H. et al.Natalizumab for active Crohn's disease.N Engl J Med. 2003; 348: 24-32Crossref PubMed Scopus (774) Google Scholar In initial randomized controlled trials, natalizumab showed efficacy in both multiple sclerosis (MS) and CD.7Polman C.H. O'Connor P.W. Havrdova E. et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 899-910Crossref PubMed Scopus (2641) Google Scholar, 9Sandborn W.J. Colombel J.F. Enns R. et al.Natalizumab induction and maintenance therapy for Crohn's disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (820) Google Scholar 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.9Sandborn W.J. Colombel J.F. Enns R. et al.Natalizumab induction and maintenance therapy for Crohn's disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (820) Google Scholar 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.10Van 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: 362-368Crossref PubMed Scopus (944) Google Scholar, 11Kleinschmidt-DeMasters B.K. Tyler K.L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.N Engl J Med. 2005; 353: 369-374Crossref PubMed Scopus (963) Google Scholar, 12Langer-Gould A. Atlas S.W. Green A.J. et al.Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.N Engl J Med. 2005; 353: 375-381Crossref PubMed Scopus (945) Google Scholar 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%.13Dong-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)PubMed Google Scholar 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.14Tan C.S. Koralnik I.J. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis.Lancet Neurol. 2010; 9: 425-437Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar Rates increased dramatically during the peak of the acquired immune deficiency syndrome epidemic, with up to 5% of individuals with acquired immune deficiency 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.10Van 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: 362-368Crossref PubMed Scopus (944) Google Scholar, 11Kleinschmidt-DeMasters B.K. Tyler K.L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.N Engl J Med. 2005; 353: 369-374Crossref PubMed Scopus (963) Google Scholar, 12Langer-Gould A. Atlas S.W. Green A.J. et al.Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.N Engl J Med. 2005; 353: 375-381Crossref PubMed Scopus (945) Google Scholar 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.15Honey K. The comeback kid: TYSABRI now FDA approved for Crohn disease.J Clin Invest. 2008; 118: 825-826Crossref PubMed Scopus (23) Google Scholar 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.16Padgett B.L. Walker D.L. ZuRhein G.M. et al.Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy.Lancet. 1971; 1: 1257-1260Abstract PubMed Scopus (1235) Google Scholar JCV antibodies later were discovered in both HIV-positive and HIV-negative individuals with PML.14Tan C.S. Koralnik I.J. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis.Lancet Neurol. 2010; 9: 425-437Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar, 17Weber F. Goldmann C. Kramer M. et al.Cellular and humoral immune response in progressive multifocal leukoencephalopathy.Ann Neurol. 2001; 49: 636-642Crossref PubMed Scopus (98) Google Scholar This human-specific ubiquitous virus often lies dormant in the kidneys, bone marrow, lymphoid tissues, and oligodendrocytes of the CNS in the immunocompetent host.14Tan C.S. Koralnik I.J. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis.Lancet Neurol. 2010; 9: 425-437Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar, 18Markowitz R.B. Thompson H.C. Mueller J.F. et al.Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects.J Infect Dis. 1993; 167: 13-20Crossref PubMed Scopus (221) Google Scholar, 19Kitamura T. Aso Y. Kuniyoshi N. et al.High incidence of urinary JC virus excretion in nonimmunosuppressed older patients.J Infect Dis. 1990; 161: 1128-1133Crossref PubMed Scopus (206) Google Scholar 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%.20Bozic 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: 299-304Crossref PubMed Scopus (69) Google Scholar 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.20Bozic 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: 299-304Crossref PubMed Scopus (69) Google Scholar, 21Olsson T. Achiron A. Alfredsson L. et al.Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort.Mult Scler. 2013; 19: 1533-1538Crossref PubMed Scopus (86) Google Scholar 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%).22Verbeeck 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: 1393-1397Crossref PubMed Scopus (50) Google Scholar In this month's issue of Clinical Gastroenterology and Hepatology, Bellaguarda et al23Bellaguarda 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: 1919-1925PubMed Google Scholar 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 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.24Bloomgren G. Richman S. Hotermans C. et al.Risk of natalizumab-associated progressive multifocal leukoencephalopathy.N Engl J Med. 2012; 366: 1870-1880Crossref PubMed Scopus (959) Google Scholar 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.24Bloomgren G. Richman S. Hotermans C. et al.Risk of natalizumab-associated progressive multifocal leukoencephalopathy.N Engl J Med. 2012; 366: 1870-1880Crossref PubMed Scopus (959) Google Scholar 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,23Bellaguarda 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: 1919-1925PubMed Google Scholar 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 al23Bellaguarda 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: 1919-1925PubMed Google Scholar 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.25Scott F.I. Osterman M.T. McConnell R.A. 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: 2625-2633Crossref PubMed Scopus (3) Google Scholar 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 second-line 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. Prevalence of Antibodies Against JC Virus in Patients With Refractory Crohn's Disease and Effects of Natalizumab TherapyClinical Gastroenterology and HepatologyVol. 13Issue 11PreviewNatalizumab, 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. Full-Text PDF
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