Does Natalizumab Therapy Benefit Patients With Multiple Sclerosis?

Doesnatalizumabtherapybenefitpatientswithmultiplesclerosis (MS)?Theobviousanswer isyes.Natalizumabwasapprovedfor patientswithrelapsingformsofMSbyregulatoryagenciesbased on the results of 2phase3 clinical trials that showedsubstantial benefitswithregardtoclinicalandparaclinicaloutcomes.1,2Post hocanalysessuggestthatmanywhoadheretonatalizumabtherapyhaveahigh likelihoodofbeingdisease free formanyyears.3 Basedontheseefficacydata,patientsshouldperhapsbetreated withnatalizumab indefinitelyoruntil theyseemtohave transitioned to secondary progressiveMS. However, shortly after its initial approval, itwasdeterminedthatnatalizumabuse isassociatedwithprogressivemultifocalencephalopathy(PML),anopportunistic infectionofthecentralnervoussystemthat iscaused by the humanpolyomavirus JohnCunninghamvirus (JCV). It isunclearwhynatalizumab increases the riskofPML,but itsmechanismofantagonizingα4 integrin–mediatedcellmigration likelydiminishes immunesurveillanceof thebrainandspinalcord.Whiledebatablylow,thisriskiscauseforconcernamong physiciansandatvarious times for somepatientsbasedontheir risktolerance.Almostsince its approval, attemptshavebeen made to determine whether discontinuationofnatalizumabissafe, inwhomtheagentshould bediscontinued,andhow.Althoughthepathogenicevents leading tonatalizumab-associatedPML remain opaque, the following3 factorsareassociatedwith theoverall riskof this infection: apositiveserostatusforanti–JCVantibodies, theutilizationof immunosuppressantsbeforeinitiatingnatalizumabuse,andthedurationofnatalizumabtherapy (aloneor incombination).4 If all 3 risk factorsarepresent, the riskofnatalizumab-associatedPML is approximately 1 in 90,which seemsunacceptably high given that PML is associatedwith ahighmorbidity andmortality and that alternative therapiesexist.Thedevelopmentof anassay to identifypatientswhoarepositive for JCVandthe identification of theotherknownrisk factors representamajorplus for initiating therapy, butwhenapatient becomespositive for JCVorhas beenonanatalizumabregimenforasubstantial amountof time anddesires to stop therapy, the path is less clear. Consequently,neurologistshavebeen investigatinghowto transition patients who want to cease natalizumab to other therapies.5,6Thegoalofa treatmentchange is2-fold,namely, to lowertheriskofPMLandtopreventMSdiseasereactivation.The riskofPMListhoughttobeabsentornegligibleforanyoftheother approvedtherapies,whereas it remainselevatedat least foraperiodafternatalizumab isdiscontinued.7Theriskofdisease reactivation is high, and it occurswithin 3 to 6months after the last natalizumabdose is administered.8 Related article page 954 Figure. PatientsWithMultiple Sclerosis Experience aMeaningful Reduction in Disease Activity During Natalizumab Therapy