ライフサイエンスコーパス: natalizumab

1 biologic agents (infliximab, adalimumab, and natalizumab).

2 -339.3, p < 0.0001) in patients treated with natalizumab.

3 multiple sclerosis (MS) who are treated with natalizumab.

4 rials established the efficacy and safety of natalizumab.

5 onance imaging MS activity after 24 doses of natalizumab.

6 score remained stable for patients receiving natalizumab.

7 died of PML after receiving 45 infusions of natalizumab.

8 66% failed treatment with natalizumab.

9 far unreported amongst patients treated with natalizumab.

10 atients treated with the monoclonal antibody natalizumab.

11 lateral blindness following his 44th dose of natalizumab.

12 cal leukoencephalopathy (PML) in patients on natalizumab.

13 or multiple sclerosis patients treated with natalizumab.

14 being treated or considering treatment with natalizumab.

15 atients with multiple sclerosis treated with natalizumab.

16 ultiple sclerosis (MS) patients treated with natalizumab.

17 ncreases with the duration of treatment with natalizumab.

18 ts given fingolimod, and 1160 patients given natalizumab.

19 ith treatment with immunosuppressors such as natalizumab.

20 eness and well-established safety profile of natalizumab.

21 r probability of disability improvement than natalizumab (0.35 [0.20-0.59], p=0.0006).

22 , fingolimod (1.27 [0.60-2.70], p=0.67), and natalizumab (0.81 [0.47-1.39], p=0.60).

23 Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of

24 imod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6).

25 es of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients).

26 total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP.

27 lity Status Scale score at the initiation of natalizumab, 3.6).

28 s received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before

29 Natalizumab, a humanized monoclonal antibody targeting a

30 INTERPRETATION: Natalizumab administered up to 9 h after stroke onset di

31 e decision was made to continue or interrupt natalizumab after 24 doses.

32 alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disabili

33 e, we review the bench-to-bedside journey of natalizumab, along with the lessons learned from postmar

34 We assessed the effect of one dose of natalizumab, an antibody against the leukocyte adhesion

35 Both natalizumab and alemtuzumab seem highly effective and vi

36 risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI inc

37 the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, resp

38 Treatment with natalizumab and fingolimod showed different compartmenta

39 d relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50%

40 d high-titer neutralizing antibodies against natalizumab and had to stop therapy.

41 ct the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk

42 ith multiple sclerosis who were treated with natalizumab and in whom PML later developed.

43 r or with approved second-line drugs such as natalizumab and mitoxantrone.

44 Natalizumab and placebo groups had similar incidences of

45 ) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab

46 ed out, the shared reason for switching from natalizumab and the preferential use of either rituximab

47 Analyses included patients on natalizumab and those who discontinued natalizumab but r

48 modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory app

49 Alemtuzumab, natalizumab, and fingolimod were associated with the gre

50 e with multiple sclerosis being treated with natalizumab, and one with rheumatoid arthritis being tre

51 n risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly h

52 Natalizumab antibody to alpha4-integrins is used in ther

53 responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNbeta-1a ar

54 The on-natalizumab ARR was 0.15, a 92.5% reduction from the yea

55 On-natalizumab ARRs were similar between patients who disco

56 pse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower

57 AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated wi

58 Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whe

59 CR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5.

60 pattern facilitates an earlier diagnosis of natalizumab-associated PML in an asymptomatic stage asso

61 18 patients with MS with natalizumab-associated PML lesions on MRI were included.

62 Asymptomatic natalizumab-associated PML manifestations on MRI show a

63 ients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC vira

64 Identifying patients with natalizumab-associated PML poses a diagnostic challenge

65 tudy assessing brain MRI of 26 patients with natalizumab-associated PML presenting with lesions sugge

66 Fortunately, natalizumab-associated PML remains a rare entity compare

67 WHERE NEXT?: Diagnosis of natalizumab-associated PML requires optimised clinical v

68 more common and more severe in patients with natalizumab-associated PML than it is in patients with H

69 ancement is the most common earliest sign of natalizumab-associated PML-IRIS with a frequent imaging

70 antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML.

71 should be included in the case definition of natalizumab-associated PML.

72 been identified that aid in the diagnosis of natalizumab-associated PML.

73 al presentation, diagnosis, and treatment of natalizumab-associated PML.

74 BACKGROUND AND Natalizumab-associated progressive multifocal leukoencep

75 constitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencep

76 lerosis who received 12 or more infusions of natalizumab at an academic multiple sclerosis center.

77 IDG discontinued natalizumab at once and initiated another disease modify

78 currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status.

79 Patients who stopped natalizumab because of poor tolerance or lack of efficac

80 l to monitor the risk incurred during use of natalizumab beyond 3 years.

81 nized anti-alpha4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the C

82 ts on natalizumab and those who discontinued natalizumab but remained in TOP.

83 Natalizumab can be a therapeutic option in patients with

84 ith severe rebound MS disease activity after natalizumab cessation.

85 sitive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources.

86 lished using sera from >800 MS patients from natalizumab clinical studies.

87 from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA usin

88 Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2

89 invasive cancer was seen with rituximab and natalizumab, compared to the general population.

90 izumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [O

91 ect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitter

92 In the as-treated group, natalizumab continuers received natalizumab, natalizumab

93 .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or

94 ncephalopathy (PML) following treatment with natalizumab develop IRIS which carries a high morbidity

95 unotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, nec

96 benefits of disease control, we initiated a natalizumab discontinuation study.

97 Natalizumab discontinuation therapy was associated with

98 therapy >/=24 months and were contemplating natalizumab discontinuation were enrolled.

99 After natalizumab discontinuation, 1 patient developed progres

100 creased risk of MS activity resumption after natalizumab discontinuation.

101 alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the bloo

102 Natalizumab dosage interruption is associated with clini

103 At the time natalizumab dosing was suspended, JCV DNA was detected i

104 utcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swe

105 imod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity.

106 apies, and natalizumab quitters discontinued natalizumab during the study year.

107 and thrombocytopenia in newborns exposed to natalizumab during the third trimester.

108 ive multiple sclerosis who were treated with natalizumab during their third trimester of pregnancy, w

109 Recently, the monoclonal antibodies natalizumab, efalizumab, and rituximab--used for the tre

110 -infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late

111 , ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late

112 ur l'Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational

113 ge, comprehensive data about third-trimester natalizumab exposure are scant.

114 Neither natalizumab exposure nor prior immunosuppressant use app

115 alence was similar in patients regardless of natalizumab exposure or prior immunosuppressant use, p =

116 mpared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients

117 We review each of the newly approved agents-natalizumab, fingolimod, teriflunomide, dimethyl fumarat

118 Treatment of multiple sclerosis with natalizumab first involves risk stratifying patients.

119 The use of natalizumab for highly active relapsing-remitting multip

120 mple was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy

121 virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS).

122 These treatments - most notably natalizumab for multiple sclerosis - have led to a surge

123 diction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly be

124 s review article summarizes the evolution of natalizumab from target molecule discovery through regul

125 Two patients in the natalizumab group died because of adverse events assesse

126 Natalizumab has been available as a multiple sclerosis t

127 Two weeks after his 45th dose of natalizumab, he developed hemiplegia that evolved into q

128 median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-ye

129 Natalizumab improves ambulatory function in disabled RRM

130 rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, a

131 e Sclerosis [AFFIRM], Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Pa

132 regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001).

133 anisms that may contribute to the benefit of natalizumab in MS, as well as candidate therapeutics tha

134 rapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).

135 ng the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis pa

136 e modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more nat

137 d at baseline, 6 and 12 months from the last natalizumab infusion.

138 natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean

139 Annual PML risks (per 12 natalizumab infusions) for patients without PML in the p

140 mab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from s

141 intervals to 10 months during the course of natalizumab infusions.

142 eucoencephalopathy reported, following 11-44 natalizumab infusions.

143 Natalizumab inhibits the trafficking of lymphocytes from

144 .001) and with less disease activity before natalizumab initiation (P = .03).

145 r median Expanded Disability Status Scale at natalizumab interruption was 3.0 and increased to 6.0 du

146 Natalizumab is an effective treatment for patients with

147 Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progres

148 Natalizumab is effective in anti-TNF failures and patien

149 le disease-modifying therapies, switching to natalizumab is more effective than switching to fingolim

150 bsample of 5 mother-child pairs, we analyzed natalizumab levels in the umbilical cord blood.

151 cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009,

152 Our data indicate that natalizumab may be safe and effective against MS in pedi

153 CV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon beta

154 The risks and benefits of natalizumab must be reassessed with continued therapy du

155 s significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natal

156 zumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natali

157 2015, 161 patients were randomly assigned to natalizumab (n=79) or placebo (n=82).

158 ncluded patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171).

159 eated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different

160 Natalizumab, no treatment, interferon beta, glatiramer a

161 modifying treatments for multiple sclerosis, natalizumab (NTZ) is highly effective, well tolerated an

162 Natalizumab (NTZ), a monoclonal antibody to human alpha4

163 ultiple sclerosis (MS) patients treated with natalizumab (NTZ).

164 The Tysabri (natalizumab) Observational Program (TOP) is an open-labe

165 Assess the effects of natalizumab on ambulatory function in disabled subjects

166 quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab contin

167 e, clinicians often switch therapy to either natalizumab or fingolimod.

168 onths immediately preceding switch to either natalizumab or fingolimod.

169 andomly assigned (1:1) to 300 mg intravenous natalizumab or placebo with stratification by treatment

170 rferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab.

171 f PML increases with duration of exposure to natalizumab over the first 3 years of treatment.

172 These data confirm that JCV in natalizumab-PML patients is similar to that observed in

173 Natalizumab prevented CNS inflammation and demyelination

174 Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3(high) IgG

175 Chemotherapy combined with Natalizumab prolonged survival of NOD/SCID recipients of

176 apse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and

177 witchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the

178 No disease rebound was observed in natalizumab quitters.

179 spended pending a safety review when several natalizumab recipients were diagnosed as having progress

180 opeller and thigh domain fragment shows that natalizumab recognizes human-mouse differences on the ci

181 In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of

182 Natalizumab reduces multiple sclerosis relapses very eff

183 ongitudinal clinical course of patients with natalizumab-related progressive multifocal leukoencephal

184 natalizumab and shorten the period in which natalizumab remains active (usually several months).

185 Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered onl

186 d treatment with the CD49d-blocking antibody natalizumab resulted in significantly decreased migratio

187 ebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset

188 ingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (inte

189 SAE data were consistent with natalizumab's known safety profile; no new safety signal

190 Interim TOP data confirm natalizumab's overall safety profile and the low relapse

191 tively analyzed data from 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing-Remitting M

192 INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised r

193 Natalizumab seems superior to alemtuzumab in enabling re

194 Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety

195 Thus patients treated with natalizumab show clinical benefit even in the presence o

196 The natalizumab story highlights both the opportunities and

197 een patients who discontinued or remained on natalizumab, suggesting limited attrition bias.

198 sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressi

199 quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79).

200 natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, an

201 ntly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protecti

202 Natalizumab, the first anti-integrin antibody tested for

203 Fingolimod and natalizumab therapies efficiently targeted autoreactive

204 with multiple sclerosis (MS) who had been on natalizumab therapy >/=24 months and were contemplating

205 r long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens.

206 n the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years

207 lopathy risk associated with >/=24 months of natalizumab therapy against the benefits of disease cont

208 n 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment,

209 The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (

210 gulated in developing B cells in response to natalizumab therapy, a known risk factor for PML.

211 immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of

212 After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8

213 After 12 months of natalizumab therapy, the prevalence of JC virus in the u

214 s of immunosuppression that may occur during natalizumab therapy.

215 In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab

216 The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in

217 In this study, switching from natalizumab to fingolimod was associated with a risk of

218 cipants were patients for whom a switch from natalizumab to fingolimod was planned.

219 ocyte traffic, was diminished in DRGs of all natalizumab-treated animals.

220 memory subsets in the blood of untreated and natalizumab-treated MS patients (n = 38).

221 A was detectable within cell compartments of natalizumab-treated MS patients after treatment inceptio

222 In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in th

223 sive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (J

224 NA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or m

225 In our evaluation of natalizumab-treated MS patients, 53.6% tested positive f

226 tomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients.

227 y in screening and early diagnosis of PML in natalizumab-treated MS patients.

228 ntly developing PML had similar NfL to other natalizumab-treated MS patients.

229 kely to be useful for predicting PML risk in natalizumab-treated MS patients.

230 ring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to

231 higher than in the pre-PML condition and in natalizumab-treated or untreated MS patients, and NfL co

232 25.6%) subjects without a difference between natalizumab-treated patients and controls.

233 Data on natalizumab-treated patients were pooled from four large

234 frequencies in untreated and fingolimod- or natalizumab-treated patients with MS.

235 characteristics of PML-IRIS manifestation in natalizumab-treated patients with multiple sclerosis and

236 We report on 20 natalizumab-treated patients with multiple sclerosis who

237 istry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, ac

238 sociated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis.

239 eactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis.

240 pse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical pract

241 The results suggest that in natalizumab-treated patients, NfL may represent an early

242 were evaluated in a single center cohort of natalizumab-treated patients.

243 ted >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-

244 rmine the presence of anti-JCV antibodies in natalizumab-treated PML patients where serum samples wer

245 Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple

246 DNA sequences in blood, CSF and/or urine of natalizumab-treated PML patients.

247 The cohort comprised 25 PML, 136 natalizumab-treated, and 151 untreated MS patients.

248 le sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response aga

249 therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (in

250 ML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS).

251 ve multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of

252 ver, severe disease activity may return once natalizumab treatment is withdrawn, as recommended durin

253 Sometimes restarting natalizumab treatment may be the best option for the mot

254 orted here sought to determine the effect of natalizumab treatment on relapse activity in the minorit

255 Natalizumab treatment resulted in a decrease in the numb

256 ults, close clinical vigilance is indicated, natalizumab treatment should be suspended, and JCV polym

257 Natalizumab treatment significantly reduced the annualis

258 itive patients who wish to begin or continue natalizumab treatment to be managed with a more individu

259 These data link the mechanism of natalizumab treatment with progressive multifocal leukoe

260 mmunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were ass

261 (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immuno

262 These analyses demonstrated that natalizumab treatment, both alone (AFFIRM) and in combin

263 Clinical data were collected on natalizumab treatment, duration and management of the wa

264 eveloped, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebel

265 thology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation,

266 t suffer this opportunistic infection during natalizumab treatment.

267 te neurological disability despite long-term natalizumab treatment.

268 atus, prior immunosuppression, and length of natalizumab treatment.

269 infections have been rarely reported during natalizumab treatment.

270 munosuppressants, and increasing duration of natalizumab treatment.

271 leukoencephalopathy (PML) is associated with natalizumab treatment.

272 tion, and 19% (16/84) had no interruption in natalizumab treatment.

273 any of these 1,094 patients before or after natalizumab treatment.

274 multifocal leukoencephalopathy (PML) during natalizumab treatment.

275 +) T lymphocytes in DRGs was not affected by natalizumab treatment.

276 and 55 (25%) were positive after 48 weeks of natalizumab, treatment.

277 f FAE and bsAb formation using Hz6F4-2v3 and natalizumab, two humanized IgG4s which bind to human Jun

278 at target the cell adhesion molecules VLA-4 (natalizumab; Tysabri for multiple sclerosis and Crohn's

279 Shortly after initial approval, natalizumab use was suspended pending a safety review wh

280 more personalized decision making and safer natalizumab use.

281 in patients being treated with rituximab or natalizumab warrants early assessment for JCV infection.

282 Median time on natalizumab was 3.3 (range 0-11.6) years; median follow-

283 l treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversi

284 l treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversi

285 Treatment with natalizumab was associated with reductions in mean annua

286 Natalizumab was detectable in all 5 newborns.

287 Natalizumab was granted approval by the US Food and Drug

288 Natalizumab was later reintroduced with required adheren

289 After the safety review, natalizumab was reintroduced to the market in 2006.

290 us success of a molecular targeted approach, natalizumab was the first mAb approved for the treatment

291 wever, only a few months after its approval, natalizumab was withdrawn from the market because of an

292 ML probability over 6 years (72 infusions of natalizumab) was 2.7% (95% CI 1.8-4.0) in patients with

293 unders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study cen

294 pha(4)beta(1) and alpha(4)beta(7) antagonist natalizumab were compared with those of the alpha(4)beta

295 n patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-

296 d leukocyte traffic by treating animals with natalizumab, which binds to alpha4-integrins.

297 Natalizumab, which binds very late antigen-4 (VLA-4), is

298 sis patients treated with the anti-VLA-4 mAb natalizumab, which selectively inhibits cell migration a

299 ere escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95

300 sociated PML and 89 MS-patients treated with natalizumab without PML.