287efficacious for anti-TNF-naive (RR, 0.87; 95% CI, 0.75–1.00) and anti-TNF-
exposed (RR, 0.86; 95% CI, 0.76–0.99) patients. Anti-α4 integrins were effective in
inducing clinical response and improving quality of life, with no significant differ-
ences between natalizumab and vedolizumab. Rates of serious adverse events, infu-
sion reactions, infections and treatment discontinuation were similar [ 21 ].
Data on the efficacy of natalizumab in UC are limited. In a pilot study evaluating the
efficacy of a single infusion of natalizumab (3 mg/kg), a significant decrease in the
median Powell-Tuck score was noted at 2 and 4 weeks (7.5 and 6, respectively) com-
pared to median baseline scores of 10. Reduction in median CRP (6 mg/L) was achieved
at 2 weeks from pretreatment levels (16 mg/L), but rescue medication was needed for
2 (20%), 3 (30%) and 8 (80%) patients by weeks 2, 4 and 8, respectively [ 22 ].
Progressive Multifocal Encephalopathy
Despite data confirming efficacy of natalizumab and also its safety profile, further
use in clinical practice was limited by the death of a patient, treated with natali-
zumab in the ENACT study, from progressive multifocal encephalopathy (PML)
[ 23 ]. Meanwhile, two other cases of PML occurred in patients with multiple sclero-
sis receiving concomitant natalizumab and interferon β1a [ 24 , 25 ]. PML is caused
by the reactivation of the latent polyoma JC virus and is related to decreased immune
surveillance and impaired diapedesis of lymphocytes across the blood-brain barrier
[ 26 ]. The earliest clinical manifestations are cognitive impairment and behavioural
changes, which progress to visual and language disturbances and also seizures, cor-
tical spinal syndrome and motor weakness [ 27 ]. Optic neuritis and spinal cord
involvement are rare. Unlike classical PML however, gadolinium-enhancing lesions
are observed at presentation in approximately 43% of patients with natalizumab-
associated PML; these are diffuse and subcortical and rarely involve the periven-
tricular region [ 28 ]. The diagnosis is confirmed by quantitative detection of JCV
DNA in the cerebrospinal fluid (CSF) using an ultrasensitive assay [ 27 ]. Serum JCV
PCR is not a useful test for either screening or diagnosis of PML. Management
options for natalizumab-induced PML are limited [ 29 ]. Natalizumab must be dis-
continued at the first clinical suspicion of PML. Plasmapheresis to remove natali-
zumab followed by accelerated desaturation of the targeted α4 integrin receptor and
restoration of leucocyte migration are recommended for up to five sessions. Antiviral
therapy with cytosine arabinoside or cidofovir and serotonin receptor antagonists
may be considered [ 29 ]. Rapid reversal of immunosuppression in cases of natali-
zumab-associated PML may result in an “immune reconstitution syndrome” which
targets JCV in the central nervous system but may result in a paradoxical worsening
of PML symptoms for which high-dose corticosteroid therapy may be required [ 29 ].
The outcome of PML is dismal, with a reported mortality of 60% in patients with at
least 6 months of follow-up [ 26 ].
All cases of natalizumab-induced PML occurred in patients who were JCV anti-
body positive. The seroprevalence of JCV-specific IgG in healthy blood donors is
16 Anti-integrin Agents in IBD: Efficacy and Risk of Complications