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PostPosted: Tue Feb 15, 2011 7:35 pm    Post subject: MS TREATMENTS: TYSABRI-RELATED TOPICS Reply with quote

This new subcategory will be for ancillary topics related to Tysabri. I may eventually transfer some earlier posts here as well but for now the starting point is today.
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PostPosted: Tue Feb 15, 2011 7:39 pm    Post subject: (Abstr.) IRIS in MS patients after stopping Tysabri Reply with quote

From Archives of Neurology, February 2011:

Quote:
ONLINE FIRST

Immune Reconstitution Inflammatory Syndrome in Patients With Multiple Sclerosis Following Cessation of Natalizumab Therapy

Augusto Miravalle, MD; Rikke Jensen, MD; R. Philip Kinkel, MD


Objective

To assess clinical consequences of temporary natalizumab dosage suspension.

Design

Prospective cohort study.

Setting

Multiple sclerosis (MS) center at an academic medical center in the United States.

Patients

Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions.

Main Outcomes Measures


Recurrent MS disease activity, defined as a clinically documented exacerbation with objective findings and/or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging.

Results

Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy (9 of 24 and 3 of 8, respectively), but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy. Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome.

Overall, relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption. The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy (r = 0.51; P = .45). Prior disease control resumed after reinstitution of natalizumab therapy in all patients.

Conclusions

In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation.


Author Affiliations:

Department of Neurology, University of Colorado, Denver (Dr Miravalle); Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark (Dr Jensen); and Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Dr Kinkel).






The abstract can be seen here.
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PostPosted: Mon Mar 07, 2011 11:50 pm    Post subject: (Abstr.) Tysabri restores evoked potentials abnormalities.. Reply with quote

From PubMed via the MS International Federation newsletter, March 1, 2011:

Quote:
Mult Scler. 2011 Feb;17(2):198-203.

Natalizumab restores evoked potential abnormalities in patients with relapsing-remitting multiple sclerosis

Meuth SG, Bittner S, Seiler C, Göbel K, Wiendl H.

1University of Wuerzburg, Germany.

Background and Objective:


The objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in a cohort study in relapsing-remitting multiple sclerosis patients.

Methods:

EP data of 44 patients examined 12  months prior to natalizumab treatment, at the timepoint of treatment initiation and 1 year later were compared. Sum scores (VEP, MEP, SEP) were evaluated and correlated with the Expanded Disability Status Scale.

Results:

Improvement of the VEP sum score was found in 33% of natalizumab-treated patients but only in 9% of the same patients prior to treatment (p = 0.041). A comparable situation was found for SEP (improvement: 32% versus 5%; worsening: 11% versus 37%; p = 0.027). For MEP no significant differences were seen (improvement: 10% versus 18%; worsening: 5% versus 29%; p = 0.60). EP recordings (VEP = SEP > MEP) have the capacity to demonstrate treatment effects of natalizumab on a functional level.

Conclusions:

Natalizumab therapy increases the percentage of patients showing stable or even ameliorated electrophysiological parameters in the investigated functional systems.

PMID: 21135021


The abstract can be seen here.
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PostPosted: Fri Mar 25, 2011 6:08 pm    Post subject: (Abstr.) De-escalation from Tysabri... Reply with quote

From PubMed, March 25, 2011:


Quote:
J Neurol. 2011 Mar 23.

De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate

Havla J, Gerdes LA, Meinl I, Krumbholz M, Faber H, Weber F, Pellkofer HL, Hohlfeld R, Kümpfel T.

Institute of Clinical Neuroimmunology, Medical Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany.

Natalizumab (NAT) is an effective therapy for relapsing-remitting multiple sclerosis (MS), but is associated with an increased risk of progressive multifocal leucoencephalopathy after 2 years therapy. Thus, NAT-treated patients often decide to stop NAT therapy after 2 years.

Reports on recurrence of disease activity after NAT discontinuation are controversial. We studied disease activity in 13 MS patients who stopped NAT therapy and either remained without disease modifying therapy (no DMT, n = 6), or switched to glatiramer acetate (GLAT, n = 7). Annual relapse rate (ARR), expanded disability status scale (EDSS), and number of patients with contrast-enhancing-lesions (Gd+) on MRI before, during and within 1 year after NAT were determined. We observed recurrence of disease activity in both groups (5/7 GLAT treated patients and 6/6 patients without DMT) within 12 months after cessation of NAT (mean time to first relapse was 5.5 months for all patients). One of the GLAT-treated patients and three patients without DMT had severe relapses with sustained EDSS worsening. No differences in ARR, EDSS and MRI parameters were seen between both groups. Patients with relapses after NAT therapy, however, tended to show higher disease activity (EDSS, ARR) before initiation of NAT therapy compared to patients without relapses. Duration of NAT treatment was not associated with higher disease activity after NAT discontinuation.

In this observation the majority of patients showed reappearance of disease activity after discontinuation of NAT regardless of whether they switched to GLAT or remained without DMT. Further treatment strategies are warranted for patients who discontinue NAT therapy.

PMID: 21431380


The abstract can be seen here.
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PostPosted: Mon Mar 28, 2011 8:03 am    Post subject: (Abstr.) Sustained improvement in EDSS... Reply with quote

From NTK Watch and PubMed, March 28, 2011:

Quote:
Mult Scler. 2011 Mar 18.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis

Phillips JT, Giovannoni G, Lublin FD, O'Connor PW, Polman CH, Willoughby E, Aschenbach W, Pace A, Hyde R, Munschauer FE.

Multiple Sclerosis Center at Texas Neurology, Dallas, Texas, USA.

Background:

Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies.

Objective:


To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies.

Methods:


Analyses were performed on patients (n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan-Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects.

Results:

Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16-2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity.

Conclusion:

These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

PMID: 21421809


The abstract can be seen here.
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PostPosted: Wed Apr 13, 2011 12:57 pm    Post subject: (AAN) Clinical outcomes in Tysabri-related PML cases Reply with quote

Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
[S51.002] Overview of Clinical Outcomes in Cases of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

Ralf Gold, Bochum, Germany, John Foley, Salt Lake City, UT, Patrick Vermersch, Lille, France, Ludwig Kappos, Basel, Switzerland, Tomas Olsson, Stockholm, Sweden, Diego Cadavid, Bedford, MA, Carmen Bozic, Sandra Richman, Cambridge, MA

OBJECTIVE:

Identify predictors of survival and functional status in postmarketing cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

BACKGROUND:

As of June 2010, 71,000 MS patients have been treated with natalizumab, corresponding to 109,100 patient-years. While natalizumab's efficacy is well known, a small number of patients experience PML, a rare opportunistic CNS infection.

DESIGN/METHODS:

Treating physicians provided PML patient updates including motor and cognitive function, ability to perform daily activities, and Karnofsky Performance Scale score. Data were supplemented by the natalizumab global safety database. PML cases were categorized by survival outcome (fatal/nonfatal) and functional status(mild/moderate/severe disability).

RESULTS:

At the time of analysis, 25/35 (71%) patients survived. Nonfatal cases were younger (median: 40 vs 54 years), had lower disability prior to PML (median EDSS: 3.5 vs 5.5), and had shorter time from PML symptom onset to diagnosis (mean: 44 vs 63 days) than fatal cases.

Survival rates varied by region (Europe 22/24, 92%; US 3/11, 27%). Most (70%) fatal cases had widespread PML on MRI. Other factors (eg, gender, MS duration, natalizumab exposure, prior immunosuppressant use, CSF JCV DNA load at diagnosis) were generally similar between groups.

In all cases, natalizumab dosing was withheld and most patients were treated by plasma exchange or immunoadsorption to rapidly remove natalizumab.

Immune reconstitution inflammatory syndrome (IRIS) was reported in most (91%) cases and was usually treated with high-dose corticosteroids.

Of PML cases with 6-month follow-up (48%) after diagnosis, 33% had mild, 33% moderate, and 33% severe disability. Available updated outcomes data will be presented.

CONCLUSIONS:

Natalizumab-associated PML has a better survival rate than PML in other populations. Improved survival was associated with younger age at diagnosis, less disability prior to PML, more localized PML on MRI, and shorter time to PML diagnosis. Earlier diagnosis and aggressive PML and IRIS management may improve outcomes. S

Supported by:

Biogen Idec Inc. and Elan Pharmaceuticals Inc.
Category - MS and Related Diseases: Clinical Science

Thursday, April 14, 2011 3:15 PM

Session S51: Multiple Sclerosis: Treatment Complications (3:00 pm-4:30 pm)




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PostPosted: Fri Apr 15, 2011 6:36 pm    Post subject: Some information on the patients with PML Reply with quote

This is the only information I've found on how the PML patients have been doing. It isn't very detailed but it at least gives a few facts.

From Bloomberg.com, April 15, 2011:

Quote:
The damage from PML, once thought to be immediately fatal, is substantial, according to another report released at the American Academy of Neurology meeting in Honolulu yesterday. Twenty-one Tysabri patients have died from PML through March 4.

Sixty-three of the first 79 Tysabri patients with the disease survived almost 10 months after diagnosis, said Patrick Vermersch, head of neurology at the University of Lille in France. Of those, 87 percent had moderate to severe disabilities, which make it difficult to keep a job or take care of oneself without help, said Kinkel, who moderated the session where the results were presented.

‘Significant Disabilities’

“It’s like the worst kind of imagined relapse,” he said. “It’s surviving, but they have significant disabilities.”



The whole article can be seen here.
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PostPosted: Sun Apr 17, 2011 9:56 am    Post subject: (AAN) "Drug holiday" vs. every other month dosing Reply with quote

Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
Natalizumab in Multiple Sclerosis: A 'Drug Holiday' Is Less Well Tolerated Than a Regimen of Every Other Month Dosing

Siddharama Pawate, Subramaniam Sriram, Nashville, TN, Harold Moses, Brentwood, TN

OBJECTIVE:

To report our experience on the tolerability of drug holiday and alternate month (q.o.m) regimen of natalizumab in multiple sclerosis (MS).

BACKGROUND:

Therapy of MS using monthly Natalizumab, a monoclonal antibody directed against alpha-4 integrin, MS carries a risk, estimated to be approximately 1:1000, of progressive multiple leukoencephalopathy (PML), caused by JC virus, with most cases occurring after 24 months.

A drug holiday, interruption of natalizumab therapy for 6 months, has been considered as a method to reduce the risk of PML. Another possible approach is to use natalizumab less frequently (once every 2 months).

DESIGN/METHODS:

A retrospective evaluation of 140 patients receiving natalizumab for MS showed that 25 patients were on a drug holiday of 6 months or more, and 22 were receiving natalizumab every other month (q.o.m.) for 6 months or longer. Their records were reviewed for patient reports of worsening, recorded neurological examinations and where available, brain magnetic resonance imaging (MRI).

RESULTS:

Of the 25 patients who were on a drug holiday, 15 were on alternative immunomodulatory therapy (glatiramer acetate, n=14 and Rebif, n=1). Of the 25 patients, 14 reported feeling worse during the holiday (4/10 of those without alternative therapy and 10/15 of those on alternative therapy), and 9 of the 14 received steroids after they were determined to have true relapses. Of the 9 MRIs available, 4 showed one or more contrast enhancing lesions.

Of the 22 patients on q.o.m. natalizumab, 9 reported feeling worse and 2 were determined t have relapses and received steroids. Of the 8 MRIs available, one showed enhancing lesions.

CONCLUSIONS:

Our results suggest that a drug holiday from natalizumab, even with alternative therapies during the holiday, is poorly tolerated. In our series, q.o.m. natalizumab is better tolerated than a drug holiday. It is not known if either approach reduces the risk of PML.
Category - MS and Related Diseases: Clinical Science


Monday, April 11, 2011 2:00 PM

Session P01: Multiple Sclerosis: Medication Safety: Long Term Follow-up (2:00 pm-6:30 pm)





The abstract can be seen here.
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PostPosted: Sun Apr 17, 2011 12:08 pm    Post subject: (AAN) Extended interval dosing of Tysabri... Reply with quote

Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
[P07.200] Extended Interval Dosing of Natalizumab: A Single Center Experience

Yazan J. Alderazi, Denise Campagnolo, Roberto Bomprezzi, Phoenix, AZ

OBJECTIVE:

To investigate the effects of extending the dosing interval on efficacy & safety in multiple sclerosis (MS) patients treated with natalizumab.

BACKGROUND:

Progressive multifocal leukoencephalopathy (PML) is a complication associated with natalizumab therapy, and to decrease its risk, the minimum effective maintenance dose should be used. We describe our experience with extending the interval between natalizumab infusions and disease activity.

DESIGN/METHODS:

This is a retrospective review of all patients with relapsing remitting multiple sclerosis treated with natalizumab in a single center between Oct-2006 and Dec-2009. At discretion of treating physician and on patient agreement, the interval was extended from monthly to 5 or 6 weeks between infusions, extended interval dosing (EID). Disease activity was assessed by surveillance MRI scanning and clinical relapses.

RESULTS:

203 consecutive patients were treated with natalizumab in the considered period. 112 patients remained on monthly dosing, while 91 patients had been switched to EID. At the time of data collection, 84 patients had been on therapy for longer than 12 months and 28 for more than 24 months. Out of 111 MRI scans obtained at follow up, 99 remained unchanged. Of these stable scans, 81 were from patients on EID and 18 on the monthly dosing. 5 clinical relapses occurred; 1 in a patient on EID.

CONCLUSIONS:

Natalizumab is effective in controlling MS as very few clinical relapses were observed in our dataset. We found that the EID did not compromise the treatment effect by clinical and MRI data. EID may be an optional regimen for maintenance natalizumab therapy as it did not result in significant breakthrough disease activity. Our data merit additional investigations on alternative maintenance therapy with natalizumab.


Category - MS and Related Diseases: Clinical Science

Thursday, April 14, 2011 2:00 PM

Session P07: Multiple Sclerosis: Interventions IV (2:00 pm-6:30 pm)





The abstract can be seen here.
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PostPosted: Thu Apr 28, 2011 5:45 pm    Post subject: (Abstr.) Antibodies against Tysabri in RRMS patients Reply with quote

From NTK, April 28, 2011:

Quote:
Mult Scler. 2011 Apr 20.

Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab

Sørensen PS, Jensen PE, Haghikia A, Lundkvist M, Vedeler C, Sellebjerg F, Koch-Henriksen N, Fogdell-Hahn A, Myhr KM, Hillert J, Gold R.
SourceDanish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark.

Background:


In the clinical trials about 9% of natalizumab- treated multiple sclerosis (MS) patients generated anti-natalizumab antibodies, of which 6% were persistent and 3% transient. The occurrence of antibodies reduced serum levels of natalizumab, decreased bio-efficacy, and abrogated the therapeutic efficacy.

Objective:

The objective was to assess the frequency of anti-natalizumab antibodies in an unselected cohort of patients from four different countries. Methods: We measured anti-natalizumab antibodies in a large cohort of 4881 unselected patients from four MS centres that systematically measured antibodies in patients treated with natalizumab. We applied the same ELISA assay developed by Biogen Idec and used in the pivotal trials of natalizumab.

Results:

Antibodies occurred in 4.5% (95% confidence interval, CI: 4.0-5.1%) of the patients, and were persistent in 3.5% (95% CI: 3.0-4.0%) and transient in 1.0% (95% CI: 0.7-1.3%) of the patients. The frequencies of permanently antibody positive patients did not show statistically significant differences between the four centres, whereas the frequencies of transiently antibody positive patients showed some variations.

Conclusion:

The frequencies of antibodies appeared to be of the same magnitude in the four centres, but might be less than in the pivotal studies of natalizumab.

PMID:21511692[PubMed - as supplied by publisher]


The abstract can be seen here.
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PostPosted: Fri May 06, 2011 1:46 pm    Post subject: (Abstr.) Disease activity return after Tysabri interruption Reply with quote

From PubMed, May 6, 2011:

Quote:
Neurology. 2011 May 4.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis

O'Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, Rudick RA, Aschenbach W, Lucas N.

Source

From the St. Michael's Hospital (P.W.O.), Toronto, Ontario, Canada; University of Rochester Medical Center (A.G.), Rochester, NY; University Hospital Basel (L.K.), Basel, Switzerland; Mt. Sinai School of Medicine (F.D.L.), New York, NY; Institute of Neurology (D.H.M.), London, UK; VU Medical Centre (C.P.), Free University Hospital, Amsterdam, the Netherlands; Cleveland Clinic Foundation (R.A.R.), Cleveland, OH; and Biogen Idec, Inc. (W.A., N.L.), Weston, MA.

BACKGROUND:

Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.

OBJECTIVES:

To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.

METHODS:

Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005.

RESULTS:

Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.

CONCLUSIONS:

Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

PMID:21543733[PubMed - as supplied by publisher]


The abstract can be seen here.
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PostPosted: Wed May 11, 2011 4:13 pm    Post subject: Re: (AAN) Clinical outcomes in Tysabri-related PML cases Reply with quote

agate wrote:
Survival rates varied by region (Europe 22/24, 92%; US 3/11, 27%). Most (70%) fatal cases had widespread PML on MRI. Other factors (eg, gender, MS duration, natalizumab exposure, prior immunosuppressant use, CSF JCV DNA load at diagnosis) were generally similar between groups.


Interesting that the survival rate was so much LOWER in the US, with TOUCH. ??

Cherie
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PostPosted: Wed May 11, 2011 4:15 pm    Post subject: Reply with quote

Agate, I am trying to find a study that was apparently presented at the Hawaii AAN meeting in April, by a Dr Fowley, re: the relevance of CD4:CD8 monitoring while on Tysabri.

Have you run into anything?

Cherie
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PostPosted: Wed May 11, 2011 5:42 pm    Post subject: Reply with quote

I did a search of the AAN abstracts from the Hawaii conference but could find nothing.

Could the study have been presented at some other conference?
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PostPosted: Wed May 11, 2011 9:33 pm    Post subject: Reply with quote

Apparently it was at that conference, but it may have been some kind of presentation. Either way, I'd think there would be an abstract.

This one you posted above was included him as an author:

agate wrote:
Presented at the AAN conference in Hawaii, April 9-16, 2011:

Quote:
[S51.002] Overview of Clinical Outcomes in Cases of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

Ralf Gold, Bochum, Germany, John Foley, Salt Lake City, UT, Patrick Vermersch, Lille, France, Ludwig Kappos, Basel, Switzerland, Tomas Olsson, Stockholm, Sweden, Diego Cadavid, Bedford, MA, Carmen Bozic, Sandra Richman, Cambridge, MA

OBJECTIVE:

Identify predictors of survival and functional status in postmarketing cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

BACKGROUND:

As of June 2010, 71,000 MS patients have been treated with natalizumab, corresponding to 109,100 patient-years. While natalizumab's efficacy is well known, a small number of patients experience PML, a rare opportunistic CNS infection.

DESIGN/METHODS:

Treating physicians provided PML patient updates including motor and cognitive function, ability to perform daily activities, and Karnofsky Performance Scale score. Data were supplemented by the natalizumab global safety database. PML cases were categorized by survival outcome (fatal/nonfatal) and functional status(mild/moderate/severe disability).

RESULTS:

At the time of analysis, 25/35 (71%) patients survived. Nonfatal cases were younger (median: 40 vs 54 years), had lower disability prior to PML (median EDSS: 3.5 vs 5.5), and had shorter time from PML symptom onset to diagnosis (mean: 44 vs 63 days) than fatal cases.

Survival rates varied by region (Europe 22/24, 92%; US 3/11, 27%). Most (70%) fatal cases had widespread PML on MRI. Other factors (eg, gender, MS duration, natalizumab exposure, prior immunosuppressant use, CSF JCV DNA load at diagnosis) were generally similar between groups.

In all cases, natalizumab dosing was withheld and most patients were treated by plasma exchange or immunoadsorption to rapidly remove natalizumab.

Immune reconstitution inflammatory syndrome (IRIS) was reported in most (91%) cases and was usually treated with high-dose corticosteroids.

Of PML cases with 6-month follow-up (48%) after diagnosis, 33% had mild, 33% moderate, and 33% severe disability. Available updated outcomes data will be presented.

CONCLUSIONS:

Natalizumab-associated PML has a better survival rate than PML in other populations. Improved survival was associated with younger age at diagnosis, less disability prior to PML, more localized PML on MRI, and shorter time to PML diagnosis. Earlier diagnosis and aggressive PML and IRIS management may improve outcomes. S

Supported by:

Biogen Idec Inc. and Elan Pharmaceuticals Inc.
Category - MS and Related Diseases: Clinical Science

Thursday, April 14, 2011 3:15 PM

Session S51: Multiple Sclerosis: Treatment Complications (3:00 pm-4:30 pm)




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Last edited by lady_express_44 on Wed May 11, 2011 9:39 pm; edited 1 time in total
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PostPosted: Wed May 11, 2011 9:35 pm    Post subject: Reply with quote

Did you have to install some software on the site in order to view the abstracts? It wouldn't give me access till I did ...
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PostPosted: Wed May 11, 2011 10:34 pm    Post subject: Reply with quote

There should be an abstract although some of the presentations had "no abstract available."

I searched for John Foley and found three abstracts but they wouldn't have been what you're looking for.

I don't recall having to install special software to see the abstracts but my registration goes back a few years. Some time ago I might have had to install something--I have no recollection of it though.
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PostPosted: Fri May 27, 2011 6:35 pm    Post subject: Gravely ill woman's husband gets pledges from Elan Reply with quote

This is a sad story, from the Irish Independent, May 27, 2011:

Quote:
Gravely ill woman's husband is given pledges on co-operation

A Sligo man whose 41-year-old wife contracted an incurable deadly brain disease while using Elan's Tysabri multiple sclerosis treatment has received assurances from the company's CEO and chairman that they'll work closely with his trust to provide detailed information on the condition.

Addressing Elan's annual general meeting yesterday, accountant Declan Walsh asked Elan management to "make all resources" available to ensure the best possible care for his wife, Natalie Murphy (right).

She's in a paraplegic state in Sligo general hospital and is unable to speak after she contracted PML in 2009 having been using Tysabri since about 2006. She's the only known Tysabri user in Ireland or the UK to have contracted the disease. PML is a known, but very rare potential risk factor associated with Tysabri. Only 124 PML cases have so far been identified among Tysabri users, while 23 of those patients have died.

Close to 60,000 people around the world are currently using Tysabri. Elan is currently rolling out a new blood test, so Tysabri patients can better weigh up the risks of taking the drug if they carry specific antibodies. Speaking to the Irish Independent following the AGM, Mr Walsh -- who established the Deferno Trust (defernotrust.org) -- said he welcomed the assurances from CEO Kelly Martin and chairman Bob Ingram that they'll follow through on his proposals.

These include the establishment of a PhD research programme into Tysabri-related PML, and the appointment of a specific patient liaison officer.

Mr Walsh's wife is a pharmacologist and at one time she worked as a product manager with drug giant GlaxoSmithKline -- the company where Mr Ingram was once vice-chairman of pharmaceuticals.

He added that Elan had failed to effectively engage with him last year when he first raised the issue of his wife's condition, which he estimates results in medical costs of about €600,000 per annum for the health service.

"There was absolutely zero interaction between Elan and ourselves. The only interaction was when she was initially diagnosed," said Mr Walsh. "I had to come here to try and make a point. My beautiful wife is dying. From the outset, I've made it quite clear I'm not interested in any legal suit."




The article can be seen here.
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PostPosted: Fri Jun 10, 2011 6:10 pm    Post subject: (Abstr.) Risk stratification of PML under Tysabri... Reply with quote

From PubMed, June 10, 2011:

Quote:
Nervenarzt. 2011 Jun 10.

[Risk stratification of progressive multifocal leukoencephalopathy under natalizumab : Recommendations for JC virus serology.]

[Article in German]

Warnke C, Adams O, Hartung HP, Gold R, Hemmer B, Hohlfeld R, Stangel M, Zipp F, Wiendl H, Kieseier BC.
SourceNeurologische Klinik, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Deutschland.

JC virus (JCV)-associated progressive multifocal leukoencephalopathy (PML) represents a rare but serious side effect of natalizumab (Tysabri®) in the treatment of patients with relapsing forms of multiple sclerosis (MS).

Two factors that may increase the risk of PML have been identified: treatment duration beyond 24 months and prior immunosuppressive therapy.

Recently determination of anti-JCV antibodies mirroring JCV infection has allowed a third factor to be added to this list, and a positive serological test has been included as a risk factor on the label of natalizumab.

Clearly, JCV serology represents a tool for PML risk stratification in MS patients treated with natalizumab. However, current data as well as the experimental development of the underlying assay have not been validated by an independent laboratory.

The present article discusses possibilities and challenges of this assay and, based on our present knowledge, provides recommendations for the clinical implementation in daily practice.

PMID:21656322


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PostPosted: Fri Jul 01, 2011 9:29 am    Post subject: (Abstr.) Effect of IMT on deep gray matter nuclei... Reply with quote

From PubMed via NTK, July 1, 2011:

Quote:
J Neuroimaging. 2011 Jun 24. doi: 10.1111/j.1552-6569.2011.00622.x.

Analysis of T2 Intensity by Magnetic Resonance Imaging of Deep Gray Matter Nuclei in Multiple Sclerosis Patients: Effect of Immunomodulatory Therapies

Pawate S, Wang L, Song Y, Sriram S.

From the Multiple Sclerosis Center, Department of Neurology (SP, SA); and Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN (LW, YS).

OBJECTIVE:

To investigate differences in T2 intensity of deep gray matter (dGM) structures by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients undergoing various immunomodulatory therapies.

BACKGROUND:

In MS, dGM T2 hypointensities by MRI are hypothesized to represent iron deposition and are known to be associated with worse disease stage as assessed by brain atrophy, cognitive and physical disability. The relation between immunotherapies and T2 intensity, however, has been not been investigated in detail.

METHODS:

A total of 255 MS patients were stratified into those on no treatment (NON, n= 45), and those on immunomodulatory treatments for ≥6 months (ie, interferon beta [IFNβ]n= 118, glatiramer acetate [GA]n= 41, natalizumab [NAT]n= 39, and mycophenolate mofetil [MMF]n= 12). T2 intensities of dentate nucleus (DN), substantia nigra (SN), red nucleus (RN), and globus pallidus (GP) were measured. Group differences in T2 intensities were assessed using a linear regression model with T2 intensities as outcome variable, treatment group as main independent variable, and clinical measures such as Expanded Disability Status Scale (EDSS) score, years of MS, and 25-feet walk time (T25-FW) as covariates. To compare T2 intensities before and after treatment in a subset of NAT-treated patients, we used the Wilcoxon signed-rank test.

RESULTS:

When adjusted for EDSS, duration of disease and T25-FW, across all deep nuclei, NAT-treated patients had significantly higher T2 intensities than untreated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), IFNβ-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), and GA-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ). In a subset of MS patients receiving NAT, there was a significant increase in T2 intensities in all the dGM nuclei after 24 months of treatment (DN p= 0.00021; SN p= <0.0001; RN p= 0.00015; GP p= 0.00011).

CONCLUSION:

Our preliminary observations suggest that long-term NAT therapy in MS patients may affect T2 intensity levels of dGM brain nuclei, hence suggesting a potential effect of NAT beyond anti-inflammatory effect. Prospective studies are warranted to provide more insights into our preliminary observations. 

PMID:21707826


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PostPosted: Sat Aug 13, 2011 8:36 am    Post subject: (Abstr.) IRIS in Tysabri-associated PML Reply with quote

From PubMed, August 13, 2011:

Quote:
Neurology. 2011 Aug 10.

Immune reconstitution inflammatory syndrome in natalizumab-associated PML

Tan IL, McArthur JC, Clifford DB, Major EO, Nath A.
SourceFrom the Department of Neurology (I.L.T., J.C.M., A.N.), Johns Hopkins School of Medicine, Baltimore, MD; Department of Neurology (D.B.C.), Washington University, St Louis, MO; and Laboratory of Molecular Medicine and Neuroscience (E.O.M.), NINDS, NIH, Bethesda, MD.

OBJECTIVE:

To study the outcome of patients with multiple sclerosis (MS) and with natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution inflammatory syndrome (IRIS).

METHODS:

MedWatch reports from Biogen-Idec (manufacturer of natalizumab, Tysabri®) were reviewed which comprised all 42 cases of natalizumab-related PML cases since its reintroduction until March 2010.

RESULTS:

All except 2 patients with natalizumab-related PML were managed by discontinuation of natalizumab and plasmapheresis/immunoadsorption (PLEX/IA). Seventeen patients had contrast enhancement of PML lesions on neuroimaging at the time of diagnosis before withdrawal/removal of natalizumab (early-PML-IRIS) and 23 patients developed contrast enhancement only after withdrawal/removal of natalizumab (late-PML-IRIS).

All patients developed IRIS. IRIS was defined as worsening of neurologic deficits during the immune reconstitution following discontinuation of natalizumab, corroborated by inflammatory changes on neuroimaging. Following PLEX/IA, JC viral load in CSF increased by >10 fold in those with early-PML-IRIS but <2 fold in late-PML-IRIS. IRIS developed earlier and was more severe in early-PML-IRIS (p < 0.05). At the last follow-up, all patients had worse EDSS scores but this was higher in patients with early-PML-IRIS compared to those with late-PML-IRIS (p > 0.05). Mortality was comparable between the 2 groups, 29.4 ± 11% vs 21.7 ± 8.8%. Corticosteroid therapy during IRIS was associated with better Expanded Disability Status Scale outcome, p < 0.05.

CONCLUSION:

Early immunologic rebound in natalizumab-associated PML has worse survival and neurologic outcome. PLEX/IA may accelerate IRIS and its impact on the final outcome is unclear. Corticosteroid therapy provides a modest benefit and needs to be systemically studied in a controlled manner in the management of natalizumab-associated PML-IRIS.

PMID:21832229


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PostPosted: Fri Aug 26, 2011 10:57 pm    Post subject: What happens when Tysabri is stopped? Reply with quote

This is referring to the study referred to on May 6 (above)(abstract given).

From PubMed, August 26, 2011:

Quote:
Expert Rev Neurother. 2011 Sep;11(9):1247-50.

What happens when natalizumab therapy is stopped?

Schaaf SM, Pitt D, Racke MK.

The Ohio State University College of Medicine, Columbus, OH 43210, USA.

Evaluation of:

O'Connor PW, Goodman A, Kappos L et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76(22), 1858-1865 (2011).

Natalizumab is an α-4 integrin antagonist used for the treatment of relapsing multiple sclerosis (MS). Concerns with the drug have arisen owing to a heightened risk of progressive multifocal leukoencephalopathy, which has caused some physicians to interrupt or stop treatment altogether.

The article under review evaluates the safety of natalizumab treatment interruption, including the rate and magnitude of the return of MS disease activity toward baseline levels by clinical and MRI measures.

The investigators found that by 4-7 months after natalizumab treatment interruption, MS disease activity began to reach baseline levels, which is consistent with the known elimination kinetics of natalizumab. The duration of prior natalizumab exposure or alternate MS treatments during interruption was demonstrated not to affect return of disease activity.

Despite nearly similar disease activity after natalizumab treatment, patients with highly active disease prior to treatment had a return of disease activity that was greater in magnitude when compared with those with less active disease.

Most significantly, the study did not show evidence of rebound following natalizumab cessation. We agree with these conclusions, but note that a subgroup of MS patients may demonstrate highly active disease after natalizumab cessation.

PMID:21864070


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PostPosted: Tue Sep 06, 2011 5:36 pm    Post subject: Tysabri-associated PML & IRIS Reply with quote

See the August 13 post about this study.

From Journal Watch Neurology, September 6, 2011:

Quote:
Natalizumab-Associated PML and IRIS

Immune reconstitution inflammatory syndrome developed in all multiple sclerosis patients with natalizumab-associated progressive multifocal leukoencephalopathy.


Natalizumab, a humanized monoclonal antibody targeting the α4-integrin receptor on leukocytes, is effective in the management of multiple sclerosis (MS) and Crohn disease. Uncommonly, through reactivation of the JC virus, it causes progressive multifocal leukoencephalopathy (PML). Patients with natalizumab-associated PML (NA-PML) have been managed with drug discontinuation and plasmapheresis or immunoadsorption (PLEX/IA), but a retrospective analysis of all 42 MedWatch reports on NA-PML in MS patients between November 2006 and March 2010 indicates that this approach is associated with neurological worsening caused by immune reconstitution inflammatory syndrome (IRIS).

The 42 patients involved all had signs of neurological deterioration developing on natalizumab; PML was confirmed by demonstration of JC virus in cerebrospinal fluid or brain tissue. Forty of the patients were treated with PLEX/IA and were included in the analysis.

All 40 patients showed initial improvement or stabilization with natalizumab discontinuation and PLEX/IA and then had paradoxical neurological worsening. Seventeen patients had contrast enhancement of PML lesions on neuroimaging before discontinuation of natalizumab (early PML-IRIS), and 23 showed it thereafter (late PML-IRIS). Neurological outcomes were worse in the patients with early PML-IRIS than in those with late PML-IRIS. Corticosteroid therapy during IRIS appeared to improve outcomes; therapy with mefloquine or mirtazapine had no significant effect.

Comment:

These data, although subject to the limitations of the MedWatch reporting system, suggest that the natural history of NA-PML is distinctly different from that of typical PML. As noted by an editorialist, corticosteroid therapy appears to improve neurological outcomes, but the optimal regimen is not yet clear.

— Richard T. Ellison III, MD

Citation(s):

Tan IL et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011 Aug 10

Berger JR. Too much of a good thing? IRIS with natalizumab-associated PML. Neurology 2011 Aug 10.


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PostPosted: Tue Oct 18, 2011 3:03 pm    Post subject: (Abstr.) Survival outcome in Tysabri-related PML cases.... Reply with quote

To be presented at the ECTRIMS conference in Amsterdam, October 20, 2011:

Quote:
MS and infections 1

Overview of survival outcome and functional status in postmarketing cases of natalizumab-associated progressive multifocal leukoencephalopathy

L. Kappos, J. Foley, R. Gold, T. Olsson, P. Vermersch, C. Bozic, D. Cadavid, N. Richert, S. Richman (Basel, CH; Salt Lake City, US; Bochum, DE; Stockholm, SE; Lille, FR; Weston, US)

Background:

As of March 2011, natalizumab has been used to treat 83,300 patients, corresponding to 148,800 patient-years. While natalizumab’s efficacy is well known, a small number of patients experience progressive multifocal leukoencephalopathy (PML), a serious opportunistic infection of the brain by JC virus (JCV).

Objective:

To identify predictors of survival and describe functional status in the first 79 postmarketing natalizumab-associated PML cases.


Methods:

PML cases were categorised by survival outcome (fatal/nonfatal) and functional status (mild/moderate/severe disability). Treating physicians provided patient information on motor and cognitive function, performance of daily activities, and Karnofsky Performance Scale score. Data were supplemented by the natalizumab global safety database.


Results:

As of 4 May 2011, 101 of 124 (81%) confirmed natalizumab-treated PML patients were alive. Of the first 79 confirmed cases analysed, the survival rate was 80% (63/79); survivors were younger (median: 43.0 vs 52.5 years) and had a shorter time to PML diagnosis (mean: 34 vs 54 days) compared with fatal cases. On magnetic resonance imaging (MRI), PML was characterised as widespread in 63% of fatal cases.

Gender, natalizumab exposure, and prior immunosuppressant use were similar between fatal and nonfatal cases. Cerebrospinal fluid JCV DNA levels at diagnosis were lower in survivors, but the difference is likely not clinically meaningful.

Natalizumab was withheld in all cases of PML and was rapidly removed by plasma exchange or immunoadsorption in most cases.

Immune reconstitution inflammatory syndrome developed in the majority of PML cases and was treated with corticosteroids.

Sixty percent (38/63) of PML survivors had >=6 months of follow-up after PML diagnosis. Of these patients, 13% had mild disability, 50% had moderate disability, and 37% had severe disability based on Karnofsky scores at the time of follow-up. The majority of patients with severe disability (12/14, 86%) had Karnofsky scores of 40, which is at the interface between moderate and severe disability.

Available updated data will be presented.

Conclusions:

Survival in patients with natalizumab-associated PML was associated with younger age, more localised PML on MRI, and more rapid PML diagnosis. Functional status in survivors ranged from mild to severe disability. These data suggest enhanced clinical vigilance leading to earlier diagnosis and optimal management of PML may improve outcomes.
-----------------------------------------------------
Supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Dr. Kappos: research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill, Biogen Idec, Boehringer Ingelheim, Elan, Genmab, Glenmark, GlaxoSmithKline, Merck Serono, MediciNova, Novartis, sanofi-aventis, Santhera, Shire, Roche, Teva, UCB, Wyeth, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Foley: consultant for Biogen Idec, Teva; honoraria from Biogen Idec, Teva. Dr. Gold: research support and honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Teva; Editor-in-Chief of Therapeutic Advances in Neurological Disorders; license fee from Biogen Idec (no future rights); research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Teva. Dr. Olsson: honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, sanofi-aventis; research support from Bayer Schering, Biogen Idec, Merck Serono, sanofi-aventis. Dr. Vermersch: consultant for and honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Teva Aventis; research support from Bayer Schering, Biogen Idec, Merck Serono, Teva Aventis. Drs. Bozic, Cadavid, Richert, and Richman: employees of Biogen Idec.



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PostPosted: Thu Nov 03, 2011 7:51 am    Post subject: Herpes encephalitis during Tysabri treatment in MS Reply with quote

From Multiple Sclerosis Journal, November 2, 2011:

Quote:
Herpes encephalitis during natalizumab treatment in multiple sclerosis

A Kwiatkowski kwiatkowski.arnaud@ghicl.net
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

J Gallois
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

N Bilbault
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

G Calais
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

A Mackowiak
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

P Hautecoeur
PRES Lille Nord de France, Uni. Catholique de Lille, Groupe Hosp. de l’Institut Catholique de Lille/Faculté Libre de Méd., Clinique de Neurologie, Lille, France

In this case report we describe the first non-fatal herpes simplex virus encephalitis (HSE) case with natalizumab for multiple sclerosis (MS). A 36-year-old woman, previously treated with immunomodulatory and immunosuppressive drugs for MS, developed acute encephalitis after 6 monthly natalizumab perfusions. Brain imaging demonstrated suggestive bi-temporal lesions. Herpes simplex virus type-1 DNA was detected in cerebrospinal fluid.

The patient improved gradually after a 21-day course of intravenous acyclovir, but neuropsychiatric changes remained 5 months later.

Our non-fatal case of HSE and other reported cases of herpes infections provide evidence of an increased risk with natalizumab and point to the need for clinicians to maintain awareness.



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PostPosted: Wed Dec 14, 2011 1:25 pm    Post subject: Anti-JC virus antibody prevalence in MS patients... Reply with quote

From PubMed, December 14, 2011:

Quote:
Ann Neurol. 2011 Nov;70(5):713-21.

Anti-John Cunningham virus antibody prevalence in multiple sclerosis patients: Baseline results of STRATIFY-1

Bozic C, Richman S, Plavina T, Natarajan A, Scanlon JV, Subramanyam M, Sandrock A, Bloomgren G.

From Biogen Idec, Inc., Cambridge, MA. Carmen.bozic@biogenidec.com.

OBJECTIVE: A study was undertaken to define the prevalence of anti-JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false-negative rate of a 2-step anti-JC virus antibody assay.

METHODS: STRATIFY-1 is an ongoing, longitudinal, observational study of relapsing MS patients in the United States who are being treated or considering treatment with natalizumab. Baseline serum and plasma samples were collected for anti-JC virus antibody detection using an analytically validated, 2-step, virus-like particle-based enzyme-linked immunosorbent assay. Urine was collected for JC virus DNA detection.

RESULTS: At baseline (n = 1,096), overall anti-JC virus antibody prevalence was 56.0% (95% confidence interval [CI], 53.0-59.0) in STRATIFY-1 patients, with an assay false-negative rate of 2.7% (95% CI, 0.9-6.2). Prevalence was significantly lower in females (53.4%; 95% CI, 49.9-56.8) than males (64.3%; 95% CI, 58.2-70.0) and increased with age, p = 0.0019 and p = 0.0001, respectively. Prevalence was similar in patients regardless of natalizumab exposure or prior immunosuppressant use, p = 0.9709 and p = 0.6632, respectively. STRATIFY-1 results were generally consistent with those observed in another large North American cohort, TYGRIS-US (n = 1,480).

INTERPRETATION: Baseline results from STRATIFY-1 are consistent with other studies utilizing this assay that demonstrate a 50 to 60% prevalence of anti-JC virus antibodies, a low false-negative rate, and an association of increasing age and male gender with increasing anti-JC virus antibody prevalence. Neither natalizumab exposure nor prior immunosuppressant use appear to affect prevalence. Longitudinal data from STRATIFY-1 will confirm the stability of anti-JC virus antibody prevalence over time.
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PostPosted: Wed Dec 21, 2011 6:38 pm    Post subject: (Abstr.) Tysabri detectable in PwMS long after stopping Reply with quote

From Multiple Sclerosis, December 21, 2011:

Quote:
Mult Scler. 2011 Dec 19. [Epub ahead of print]

Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped

Rispens T, Vennegoor A, Wolbink GJ, Polman CH, Killestein J.

Sanquin Research/Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, The Netherlands.

Natalizumab is frequently used as a treatment for multiple sclerosis (MS). The occurrence of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients indicates that its prominent beneficial effects need to be balanced against the risks. Also, cessation of the drug seems to be associated with recurrence of disease activity.

Both the moment of rebound disease activity and the outcome of PML are related to clearance of the drug. Specific features of this IgG4 antibody (i.e. half-antibody exchange) may result in underestimated drug levels.

Here, we demonstrate natalizumab levels in 10 patients with relapsing MS, using a recently developed sensitive assay. Remarkably, natalizumab was detectable up to 200 days after cessation of therapy.

PMID:22183929
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PostPosted: Fri Jan 20, 2012 6:04 pm    Post subject: FDA OKs PML risk test for patients on Tysabri Reply with quote

From MedPage Today, January 20, 2012:

Quote:
FDA OKs PML Risk Test for Patients on Tysabri

By Kristina Fiore, Staff Writer, MedPage Today


The FDA has approved the first test for assessing the risk of progressive multifocal leukoencephalopathy (PML) in patients on natalizumab (Tysabri).

The Stratify JCV Antibody ELISA test screens for the presence of antibodies to the JC virus, a risk factor for PML in patients with multiple sclerosis or Crohn's disease who are taking the monoclonal antibody, the agency said in a statement.

Natalizumab was pulled from the U.S. market in 2005 after the first of some 200 cases of PML came to light, but it was allowed back on the market in 2006 after the development of a risk evaluation and mitigation strategy (REMS).

Risk of PML should be calculated not only by the antibody test results, but should also be based on the length of time the patient has been on natalizumab (more than two years increases the risk) and if the patient is taking other immunosuppresants, the FDA said.

Risk of developing PML is greatest -- about 11 in 1,000 -- if a patient has all three of these risk factors.

The agency warned that the test shouldn't be used alone in making a clinical decision about the risks and benefits of continuing on natalizumab treatment, and it is not diagnostic of PML.

The agency simultaneously updated the drug's warning label to reflect the new combination of risk factors for the disease.

Although many people are infected with the JC virus at some point in their lives, it's normally kept in check by the immune system, the agency said. However, biologic drugs may promote activation of the virus in immunocompromised patients.

A total of 201 cases of PML have been reported among approximately 96,582 patients treated with natalizumab through Jan. 4, 2012, the agency said, adding that there's currently no treatment, prevention, or cure for the condition.

The FDA reviewed the antibody test via the de novo reclassification process, an approval pathway for low- to moderate-risk devices that aren't comparable to anything already available on the market.

It's made by Focus Diagnostics and comarketed by Biogen Idec and Elan.


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PostPosted: Sun Jan 29, 2012 12:27 am    Post subject: Study to evaluate Tysabri as SPMS treatment Reply with quote

A press release from Elan/Biogen, January 26, 2012:

Quote:
ASCEND Study to Evaluate the Effectiveness of TYSABRI® (natalizumab) as a Treatment for Secondary-Progressive Multiple Sclerosis

Press Release: Elan Corporation, plc – Thu, Jan 26, 2012 8:00 AM EST

WESTON, Mass. & DUBLIN--(BUSINESS WIRE)-- Biogen Idec... and Elan Corporation ... today announced a global Phase 3b study, ASCEND, that is being conducted to evaluate the effectiveness of TYSABRI as a treatment for secondary-progressive multiple sclerosis (SPMS). According to the National Multiple Sclerosis Society, approximately half of all people initially diagnosed with relapsing-remitting multiple sclerosis (RRMS) - the most common form of multiple sclerosis (MS) - will transition to SPMS within 19 years.


Patients with RRMS typically experience unpredictable relapses; the time between relapses is characterized by full or partial recovery and a lack of disease progression. SPMS is characterized by a steady progression of nerve damage, symptoms and disability, but the exact reasons for the progression are unknown. The potential for greater disease burden in SPMS typically includes decreased mobility, impaired activities of daily living, loss of independence and reduced quality of life.

"There are limited treatment options available to people living with SPMS and there is a high unmet need for effective therapies,” said Aaron Miller, M.D., member of the ASCEND advisory board; Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis; and Co-Director of the Multiple Sclerosis Care Center at Maimonides Medical Center in Brooklyn, New York. “The ASCEND trial is investigating whether treatment with TYSABRI may prevent worsening in walking, hand movement and daily functioning in these patients.”

"One hypothesis behind the development of SPMS is that disease progression is a result of chronic inflammation in the brain tissue trapped behind the blood-brain-barrier. This causes destruction of the myelin sheath which protects the coating around nerve fibers, as well as the progressive loss of nerve cells, which can lead to disability in MS patients,” said Professor Richard Reynolds, Professor of Cellular Neuroscience, Imperial College, London; and Scientific Director of the UK Multiple Sclerosis Society Tissue Bank. “Preliminary data suggest that TYSABRI may hinder this inflammation in the brain and reduce SPMS-related disease progression; therefore, further investigation of this hypothesis is warranted."

The ASCEND study is part of the ongoing commitment of both Biogen Idec and Elan to find ways to improve the well-being of patients with multiple sclerosis.

About the ASCEND Study

ASCEND (A Study to Characterize the Efficacy of Natalizumab on Disability in SPMS) is a double-blind, placebo-controlled study with SPMS patients being randomized to receive either TYSABRI 300 mg or placebo intravenously every four weeks for 96 weeks. A global study, ASCEND is expected to enroll approximately 850 patients in 15 countries.
Study participants will be between the ages of 18 and 58, inclusive, with a diagnosis of SPMS for at least two years; an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, inclusive; MS Severity Score of 4 or higher; documented, confirmed evidence of disease progression, independent of clinical relapses during the one-year prior to enrollment; and naïve to TYSABRI treatment.
The primary endpoint is to investigate whether treatment with TYSABRI slows the accumulation of disability not related to relapses in subjects with SPMS.
Secondary endpoints are:

•The proportion of subjects with consistent improvement in Timed 25-foot Walk (T25FW);
•The change in subject-reported ambulatory status as measured by the 12-Item MS Walking Scale (MSWS-12);
•The change in manual ability based on the ABILHAND questionnaire;
•The impact of TYSABRI on subject-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical);
•The change in whole brain volume between the end of study and week 24 using MRI; and
•The proportion of subjects experiencing progression of disability as measured by individual physical EDSS system scores.
ASCEND is ongoing and actively enrolling patients. Patients interested in learning more about the study may speak with their physician or e-mail neurologyclinicaltrials@biogenidec.com.





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PostPosted: Tue Feb 28, 2012 7:26 pm    Post subject: JCV test for Tysabri users approved Reply with quote

From Journal Watch Neurology Alert, February 28, 2012:

Quote:
NEWS IN CONTEXT

JC Virus in Natalizumab Users: Test for Virus Exposure Approved

Jeffrey M. Gelfand, MD

Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS.


Patients with multiple sclerosis (MS) or Crohn disease who are taking natalizumab face an increased risk for progressive multifocal leukoencephalopathy (PML) if they have been exposed to JC virus, the FDA warned in January. The agency also announced approval of a new blood test to detect JC virus antibodies.

JC virus is common and usually harmless, the agency said, but its presence can be dangerous in patients taking immunomodulating drugs like natalizumab. Other risk factors associated with developing PML while on natalizumab are treatment with natalizumab for longer than 2 years and previous treatment with immunosuppressant drugs such as methotrexate or cyclophosphamide (but not prior use of first-line injectable immunomodulatory agents, interferon-beta, or glatiramer acetate).

The FDA estimates that patients with all three risk factors face about a 1% risk for PML with natalizumab therapy (11 cases per 1000 patients treated).

Natalizumab's label will be changed to reflect the new information.

Comment:

Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS. The risk for PML with natalizumab was previously said to be about 1 in 1000, but recent safety data provided by the manufacturer indicate that the overall incidence of PML is more than double that (2.11 per 1000 as of February 2012). The major advance for patient safety is recognition that the PML risk can be stratified by three risk factors (treatment duration >2 years, prior immunosuppressant use, and JC virus antibody seropositivity). As highlighted by the FDA, in patients with all three risk factors, the risk for PML is very high (>1 in 100). On the other end of the spectrum, the PML risk with natalizumab appears to be quite low in patients who are JC virus–seronegative. For these patients, the manufacturer estimates the PML risk to be about 1 in 10,000, with a 95% confidence interval potentially as high as 1 in 2000 and as low as zero, based on the lack of observed PML cases in JC virus–seronegative patients to date and the false-negative rate of the assay (3%). The seroconversion rate for JC virus in MS patients is about 2% per year; the optimal frequency of testing for the virus in patients taking natalizumab remains to be defined. This is a fast-moving field, so further refinement of these numbers is likely as more safety data become available.

— Jeffrey M. Gelfand, MD

Dr. Gelfand is a Clinical Instructor at the UCSF Multiple Sclerosis Center, Department of Neurology, San Francisco.

Citation(s):

Food and Drug Administration. Tysabri (natalizumab): Drug safety communication — New risk factor for progressive multifocal leukoencephalopathy (PML). Jan 20 , 2012. (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm288602.htm)

FDA permits marketing of first test for risk of rare brain infection in some people treated with Tysabri [press release]. Silver Spring, MD: Food and Drug Administration; Jan 20 , 2012. (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm288471.htm)


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PostPosted: Sat Mar 03, 2012 6:27 pm    Post subject: Tysabri discontinuation after PML risk stratification Reply with quote

Abstract from PubMed, March 3, 2012:

Quote:
Mult Scler. 2012 Mar 1.

Natalizumab discontinuation after PML risk stratification: outcome from a shared and informed decision

Tur C, Tintoré M, Vidal-Jordana A, Castilló J, Galán I, Río J, Arrambide G, Comabella M, Arévalo MJ, Horno R, Vicente MJ, Caminero A, Nos C, Sastre-Garriga J, Montalban X.

Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, Barcelona, Spain.


Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more.

The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing-remitting multiple sclerosis.

We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed.

Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment (p=0.027). In groups A and B, discontinuation also depended upon doctors' views (p=0.019, group A; p=0.010, group B) and clinical outcomes (p=0.021, group A).

No one from low-intermediate risk groups discontinued.

The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors' idiosyncrasies play a crucial part in patients' final choice.

PMID:22383232


The abstract can be seen here.
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PostPosted: Wed Mar 14, 2012 6:25 pm    Post subject: (Abstr.) ["Extended interval dosing" for Tysabri?] Reply with quote

These researchers are suggesting that "extended interval dosing" for Tysabri might be a way to protect patients against PML.

From Therapeutic Advances in Neurological Disorders, March 12, 2012:

Quote:
From injection therapies to natalizumab: views on the treatment of multiple sclerosis

Roberto Bomprezzi
Darin T. Okuda
Yazan J. Alderazi
Olaf Stüve
Elliot M. Frohman

Roberto Bomprezzi, MD, PhD, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 500 West Thomas Road, Phoenix, AZ 85013, USA rbomprezzi@chw.edu

Darin T. Okuda, MD and Yazan J. Alderazi, MD, Division of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

Olaf Stüve, MD, PhD, Elliot M. Frohman, MD, PhD, Departments of Neurology and Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Discoveries of the mechanisms that underlie the pathogenesis of multiple sclerosis have been acquired at an impressive rate over the last few decades and, as a consequence, a growing number of treatments are becoming available for this disease.

This review first analyzes the experience from the early stages of the disease-modifying therapies, then, expanding on the concept of early treatment for improved outcomes, it focuses on natalizumab and its major complication, progressive multifocal leukoencephalopathy.

We offer views on the risks associated with the use of natalizumab by underscoring the importance of the JC virus serology and by providing preliminary data on our experience with the extended interval dosing of natalizumab.

This approach, which advocates individualized treatment plans, raises the question of the minimum effective natalizumab dose. Extended interval dosing suggests efficacy can be maintained while providing advantages of costs and convenience over regular monthly dosing.

More data examining this strategy are necessary.



The abstract can be seen here.
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PostPosted: Fri Mar 23, 2012 6:22 pm    Post subject: (Abstr.) Inflammatory activity & brain atrophy... Reply with quote

From PubMed via NTK Institute, March 23, 2012:

Quote:
Eur J Radiol. 2012 Mar 3.

The relationship between inflammatory activity and brain atrophy in natalizumab treated patients

Magraner M, Coret F, Casanova B.
Multiple Sclerosis Unit, Neurology Service, Hospital Universitari i Politècnic La Fe, Bulevar Sur s/n, 46026 Valencia, Spain.

OBJECTIVE:

To assess the evolution of brain atrophy and its relationship with inflammatory activity in RRMS patients treated with natalizumab.

METHODS:

Eighteen RRMS patients were prospectively followed up for 18 months after starting natalizumab therapy. Patients were monitored monthly and assessed for signs of relapses, adverse events or disability increase. MRI scans were performed before starting natalizumab and every six months. Cross-sectional T2 lesion volume (T2LV) and the normalized brain volume (NBV) at baseline and 18 months MRI scans were calculated using the Steronauta(®) and SIENAx softwares, respectively. Longitudinal Percentage of Brain Volume Change (PBVC) was estimated with SIENA. Linkage between inflammatory activity and brain atrophy was studied.

RESULTS:

Natalizumab reduced ARR by 67% and cumulative CEL by 87.5%. T2 lesion volume decreased from 1000mm(3), to 960mm(3) (p=0.006) and NBV decreased from 1.55×10(5)mm(3) to 1.42×10(5) mm(3) (p=0.025). Global PBVC from baseline to 18 months was -2.5%, predominantly during the first six months (0-6 months PBVC -1.7%; 6-12 months PBVC -0.74%; 12-18 months PBVC -0.50%). The number of relapses before treatment was correlated to the PBVC during the first semester (Pearson's coefficient -0.520, p=0.003), while the number of basal CEL or baseline T2LV did not correlate with brain atrophy rate. During follow-up, nine patients had clinical or radiological inflammatory activity. Their PBVC was significantly higher in the first semester (-2.3% to -1.1%, p=0.002).

CONCLUSIONS:

Natalizumab reduced relapse rate and CEL in MRI. Brain atrophy predominated in the first semester and was related to previous inflammatory activity.

PMID:22391507
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PostPosted: Thu Apr 19, 2012 6:19 pm    Post subject: (Abstr.) Advances in PML management:: focus on Natalizumab Reply with quote

From PubMed, April 19, 2012:

Quote:
Cleve Clin J Med. 2011 Nov;78 Suppl 2:S33-7.

Advances in the management of PML: focus on natalizumab

Fox R.

Mellen Center for Multiple Sclerosis, Cleveland Clinic, 9500 Euclid Ave., U10, Cleveland, OH 44195, USA. foxr@ccf.org

Progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the central nervous system, occurs mainly in the setting of broad-based and selective immunosuppression. The immunomodulatory agent most often implicated in the development of PML is the monoclonal antibody natalizumab.

Management of PML begins with risk stratification. Factors that predict the risk of PML are JC virus (JCV) antibody status, history of chemotherapy use, and cumulative exposure to natalizumab. The risk of natalizumab-related PML increases up to a duration of 36 months of therapy, after which the risk appears to level off. If suspicious for PML, the use of a sensitive JCV polymerase chain reaction assay permits early diagnosis.

Immune reconstitution represents the mainstay of treatment for PML. With rapid reversal of immunosuppression followed by immunologic recovery, almost all patients suffer clinical deterioration termed immune reconstitution inflammatory syndrome (IRIS). High-dose corticosteroids are often recommended if a clinical and imaging syndrome resembling IRIS develops after immune restoration.

PMID:22123933


The abstract can be seen here.
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PostPosted: Mon Apr 23, 2012 6:15 pm    Post subject: Clinical trial of Tysabri in SPMS Reply with quote

From Rocky Mountain MS Center eNews, April 23, 2012:

Quote:
Clinical Trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis (SPMS) (ASCEND In SPMS)

This is a phase 3b, multicenter, international, randomized, double-blind, placebo-controlled study to assess the efficacy of natalizumab in approximately 856 SPMS subjects who are exhibiting disease progression independent of relapses. Subjects will be randomized to receive either natalizumab 300 mg or placebo intravenously (IV) every 4 weeks (q4wk) for 96 weeks.

This study will be conducted in subjects between the ages of 18 and 58, inclusive, with a diagnosis of SPMS for at least 2 years, an EDSS score between 3.0 and 6.5, inclusive, and documented evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment, and who are naïve to natalizumab.


The study Website is here.
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PostPosted: Mon May 07, 2012 7:03 pm    Post subject: (Abstr.)Simultaneous PML-IRIS after discontinuing Tysabri... Reply with quote

From PubMed via NTK, May 7, 2012:

Quote:
Neurology. 2012 May 1;78(18):1390-3.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Gheuens S, Smith DR, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ.

Correspondence & reprint requests to Dr. Koralnik: ikoralni@bidmc.harvard.edu.

OBJECTIVE:

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons.

CASE REPORTS AND RESULTS:

The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures.

CONCLUSIONS:

New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

PMID:22517104
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PostPosted: Fri May 18, 2012 4:02 pm    Post subject: (Abstr.) Risk of Tysabri-associated PML Reply with quote

An article about the risks of PML has appeared in the New England Journal of Medicine. Support for the article came from Biogen-Idec. The abstract is from PubMed, May 18, 2012:

Quote:
N Engl J Med. 2012 May 17;366(20):1870-80.

Risk of natalizumab-associated progressive multifocal leukoencephalopathy

Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C.

Biogen Idec, Weston, MA, USA. gary.bloomgren@biogenidec.com

BACKGROUND:

Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. We quantified the risk of PML in patients with multiple sclerosis, according to the presence or absence of three risk factors: positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increasing duration of natalizumab treatment.

METHODS:

We used data from postmarketing sources, clinical studies, and an independent Swedish registry to estimate the incidence of PML among natalizumab-treated patients with multiple sclerosis, according to positive or negative status with respect to anti-JC virus antibodies, prior or no prior use of immunosuppressants, and duration of treatment (1 to 24 months vs. 25 to 48 months). Blood samples were available for anti-JC virus antibody testing from 5896 patients with multiple sclerosis and from 54 patients with multiple sclerosis who were treated with natalizumab and in whom PML later developed.

RESULTS:

As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti-JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti-JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti-JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]).

CONCLUSIONS:

Positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination, were associated with distinct levels of PML risk in natalizumab-treated patients with multiple sclerosis.

(Funded by Biogen Idec and Elan Pharmaceuticals.).

Comment in
N Engl J Med. 2012 May 17;366(20):1938-9.
PMID:22591293
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PostPosted: Tue May 22, 2012 6:07 pm    Post subject: (Abstr.) Herpes encephalitis during Tysabri treatment in MS Reply with quote

From Multiple Sclerosis Journal, June 2012:

Quote:
Herpes encephalitis during natalizumab treatment in multiple sclerosis

A Kwiatkowski
J Gallois
N Bilbault
G Calais
A Mackowiak
P Hautecoeur

PRES Lille Nord de France, Université Catholique de Lille, Groupe Hospitalier de l’Institut Catholique de Lille / Faculté Libre de Médecine, Clinique de Neurologie, Lille, France

Dr Arnaud Kwiatkowski, Service de Neurologie, Hôpital Saint Vincent de Paul, GHICL, Boulevard de Belfort BP 387, F-59020 LILLE cedex, France. Email:

In this case report we describe the first non-fatal herpes simplex virus encephalitis (HSE) case with natalizumab for multiple sclerosis (MS).

A 36-year-old woman, previously treated with immunomodulatory and immunosuppressive drugs for MS, developed acute encephalitis after 6 monthly natalizumab perfusions. Brain imaging demonstrated suggestive bi-temporal lesions. Herpes simplex virus type-1 DNA was detected in cerebrospinal fluid.

The patient improved gradually after a 21-day course of intravenous acyclovir, but neuropsychiatric changes remained 5 months later.

Our non-fatal case of HSE and other reported cases of herpes infections provide evidence of an increased risk with natalizumab and point to the need for clinicians to maintain awareness.



The abstract can be seen here.
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PostPosted: Thu Aug 30, 2012 7:45 am    Post subject: (Abst.) MRI-based analysis of Tysabri therapeutic window Reply with quote

From Multiple Sclerosis Journal, August 29, 2012:

Quote:
MRI-based analysis of the natalizumab therapeutic window in multiple sclerosis

Luigi ME Grimaldi1
Luca Prosperini2
Gaetano Vitello1
Giovanna Borriello2
Federica Fubelli2
Carlo Pozzilli2

1U.O. Neurology, Multiple Sclerosis Centre, Fondazione Istituto San Raffaele “G. Giglio,” Italy
2Multiple Sclerosis Centre, Department of Neurology and Psychiatry, S. Andrea Hospital, Sapienza University, Italy
Carlo Pozzilli, Multiple Sclerosis Centre, S. Andrea Hospital, Department of Neurology and Psychiatry, Sapienza University, Viale dell’Università, 30 - 00185, Rome, Italy. Email:

The recommended natalizumab dosage is 300 mg every 4 weeks. We evaluated radiological activity at various times from the last natalizumab infusion by examining 386 magnetic resonance imaging (MRI) scans from 166 natalizumab-treated patients with relapsing–remitting MS.

Of 113 scans performed >4 weeks after last natalizumab infusion, 26 were active (i.e. had ≥1 contrast-enhancing lesions).

Risk of radiological activity increased by 1.34 fold for each week of delay with respect to the recommended 4-week dosing interval, compared with schedule-adherent patients (p<0.0001).

Our data suggest that an increased MRI activity ≥7 weeks from the last infusion of natalizumab should be considered in cases of therapy discontinuation.



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PostPosted: Mon Oct 08, 2012 6:18 pm    Post subject: Improved ability to work after 1 yr. on Tysabri Reply with quote

From PubMed, September 27, 2012:

Quote:
Mult Scler. 2012 Sep 25.

Improved ability to work after one year of natalizumab treatment in multiple sclerosis. Analysis of disease-specific and work-related factors that influence the effect of treatment.

Wickström A, Nyström J, Svenningsson A.

Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden.

BACKGROUND:

Multiple sclerosis (MS) constitutes one of the major diseases that leads to neurological impairment and as a consequence also reduces ability to work.

OBJECTIVES:

The purpose of this study was to analyze possible effects on work ability resulting from highly active anti-inflammatory treatment in MS.

METHODS:

We analyzed the effects of introducing an anti-inflammatory treatment, natalizumab, in MS, on factors related to work ability. This was done through a comprehensive questionnaire distributed to all patients in Sweden starting on natalizumab treatment between June 2007 and May 2008, identified via the Swedish National MS registry.

RESULTS:

MS patients who were receiving sickness benefit and were treated with natalizumab approximately doubled their working ability in relation to their total employment rate. We also documented a significant improvement of their ability to cope with work-related requirements after one year of natalizumab treatment, an improvement which was independent of the previous level of employment. Predictors of a positive effect on work ability were short disease duration, younger age and lower Expanded Disability Status Scale (EDSS) grade at treatment onset.

CONCLUSIONS:

Our data support the notion that early inflammatory control in MS is essential to preserve a healthy state in MS that counteracts the negative consequences of the disease both at a personal and at a societal level.

PMID:23012254


The abstract can be seen here.
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PostPosted: Sat Oct 27, 2012 5:38 pm    Post subject: (Abst.) Lethal MS relapse after Tysabri withdrawal Reply with quote

This is grim.

From PubMed, October 27, 2012:

Quote:
Neurology. 2012 Oct 24.

LETHAL MULTIPLE SCLEROSIS RELAPSE AFTER NATALIZUMAB WITHDRAWAL

Rigau V, Mania A, Béfort P, Carlander B, Jonquet O, Lassmann H, Camu W, Thouvenot E.

From Service d'Anatomopathologie (V.R.), Département de Réanimation Médicale (P.B., O.J.), and Département de Neurologie (B.C., W.C.), CHRU de Montpellier, Université Montpellier I, Montpellier; Service de Neurologie (A.M.), CH de Béziers, Béziers, France; Center for Brain Research (H.L.), Medical University of Vienna, Vienna, Austria; and Service de Neurologie (E.T.), CHU de Nîmes, Université Montpellier I, Nîmes, France.

Natalizumab dramatically reduces relapses in patients with active multiple sclerosis (MS), but it may induce progressive multifocal leukoencephalopathy (PML).(1) A rebound of MS or an immune reconstitution inflammatory syndrome (IRIS) [was] described after natalizumab withdrawal, even in the absence of PML.(2,3)

Very few data concerning the potential severity and the neuropathology of this event are available. We report the case of a 50-year-old patient with MS who developed a fulminating relapse 3 months after stopping natalizumab, leading to death despite intensive care and immunosuppressive therapy.

Radiologic and neuropathologic findings provide interesting data regarding the nature of the rebound.

PMID:23100404


The abstract can be seen here.
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PostPosted: Sun Dec 23, 2012 7:08 pm    Post subject: (Abst.) PML w/repeated negative JC virus testing Reply with quote

From PubMed,December 21, 2012:

Quote:
Int J Neurosci. 2012 Dec 20.

A case of natalizumab-associated progressive multifocal leukoencephalopathy with repeated negative CSF JC virus testing

Mazda ME, Brosch JR, Wiens AL, Bonnin J, Kamer AP, Mattson DH, Snook RJ.

aIndiana University School of Medicine, Department of Neurology.

The development of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab is a well-known potential risk. Diagnosis of PML can be confounded in patients with multiple sclerosis (MS) if new demyelinating lesions develop, and the sensitivity of existing diagnostic tests is less than ideal.

In the case presented here, four samples of cerebrospinal fluid were negative for JC virus DNA by polymerase chain reaction, yet brain biopsy eventually proved positive by immunohistochemistry. A review of the limitations of existing clinical diagnostic tests is addressed, and we review the most recent literature on the proper management of natalizumab-treated MS patients.

PMID:23252596
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PostPosted: Tue Jan 08, 2013 7:25 pm    Post subject: (Abst.) Tysabri's effects appear early in treatment course Reply with quote

From PubMed, January 8, 2013:

Quote:
J Neurol. 2013 Jan 5.

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course

Kappos L, O'Connor PW, Polman CH, Vermersch P, Wiendl H, Pace A, Zhang A, Hotermans C.

Departments of Neurology and Biomedicine, University Hospital Basel, Petersgraben 4, Basel, Switzerland, lkappos@uhbs.ch.

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible.

In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects.

To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri(®) Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3 months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p < 0.0001) and in patients with highly active disease (0.30 vs. 0.94; p = 0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95 % CI 0.34-0.52); p < 0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0-3 months 0.26; p < 0.0001).

Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3 months of treatment even in patients with more active disease.

PMID:23292204
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PostPosted: Sat Jan 12, 2013 11:58 pm    Post subject: (Abst.) Tysabri & ambulatory improvement in SPMS... Reply with quote

From PubMed, January 12, 2013:

Quote:
PLoS One. 2013;8(1):e53297.

Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis

Cadavid D, Jurgensen S, Lee S.

MS Clinical Development Group, Biogen Idec, Cambridge, Massachusetts, United States of America.

BACKGROUND:

There is an unmet need for disease-modifying therapies to improve ambulatory function in disabled subjects with multiple sclerosis.

OBJECTIVES:

Assess the effects of natalizumab on ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS).

METHODS:

We retrospectively reviewed ambulatory function as measured by timed 25-foot walk (T25FW) in clinical trial subjects with an Expanded Disability Status Scale score ≥3.5, including RRMS subjects from the phase 3 AFFIRM and SENTINEL trials, relapsing SPMS subjects from the phase 2 MS231 study, and nonrelapsing SPMS subjects from the phase 1b DELIVER study.

For comparison, SPMS subjects from the intramuscular interferon beta-1a (IM IFNβ-1a) IMPACT study were also analyzed.

Improvement in ambulation was measured using T25FW responder status; response was defined as faster walking times over shorter (6-9-month) or longer (24-30-month) treatment periods relative to subjects' best predose walking times.

RESULTS:

There were two to four times more T25FW responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNβ-1a arms. Responders walked 25 feet an average of 24%-45% faster than nonresponders.

CONCLUSION:

Natalizumab improves ambulatory function in disabled RRMS subjects and may have efficacy in disabled SPMS subjects. Confirmation of the latter finding in a prospective SPMS study is warranted.

PMID:23308186


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PostPosted: Mon Jan 21, 2013 5:56 pm    Post subject: (Abst.) Lessons learned from fatal PML in MS pt. on Tysabri Reply with quote

From JAMA Neurology [formerly Archives of Neurology], January 21, 2013:

Quote:
Observation |
ONLINE FIRST

Lessons Learned From Fatal Progressive Multifocal Leukoencephalopathy in a Patient With Multiple Sclerosis Treated With Natalizumab

Aaron L. Boster, MD; Jacqueline A. Nicholas, MD; Ilir Topalli, PhD; Yaz Y. Kisanuki, MD; Wei Pei, PhD; Bethanie Morgan-Followell, MD; Claudia F. Kirsch, MD; Michael K. Racke, MD; David Pitt, MD

Objective

To describe the clinical, radiological, and histopathological features of a fatal case of progressive multifocal leukoencephalopathy (PML) in a patient with multiple sclerosis treated with natalizumab. We will use this case to review PML risk stratification and diagnosis.

Design

Case report.

Setting

Tertiary referral center hospitalized care.

Patient

A 55-year-old, JC virus (JCV) antibody–positive patient with multiple sclerosis who died of PML after receiving 45 infusions of natalizumab.

Main Outcome Measures

Brain magnetic resonance imaging and cerebrospinal fluid JCV DNA polymerase chain reaction results.

Results

The patient developed subacute onset of bilateral blindness following his 44th dose of natalizumab. Ophthalmologic examination was normal, the brain magnetic resonance imaging was not suggestive of PML, and cerebrospinal fluid analysis did not reveal the presence of JCV DNA. The patient was subsequently treated for a presumed multiple sclerosis relapse with high-dose corticosteroids.

Two weeks after his 45th dose of natalizumab, he developed hemiplegia that evolved into quadriparesis. Repeated magnetic resonance imaging and cerebrospinal fluid studies were diagnostic for PML. Postmortem histopathological analysis demonstrated PML-associated white matter and cortical demyelination.

Conclusions

The risks and benefits of natalizumab must be reassessed with continued therapy duration. When there is high clinical suspicion for PML in the setting of negative test results, close clinical vigilance is indicated, natalizumab treatment should be suspended, and JCV polymerase chain reaction testing and brain magnetic resonance imaging scans should be repeated.



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PostPosted: Mon Feb 11, 2013 3:03 pm    Post subject: MS patient dies from anti-Tysabri antibodies Reply with quote

From MedPage Today, February 10, 2013:

Quote:
MS Patient Dies from Anti-Drug Antibodies

By John Gever, Senior Editor, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner


A reaction to anti-natalizumab (Tysabri) antibodies appears to have killed a Swedish woman with multiple sclerosis who received the drug, researchers said.

Significant neurological abnormalities developed after she had received six infusions of natalizumab, and her doctors found that she had extremely high titers of antibodies against the drug, reported Anders Svenningsson, MD, PhD, of Umeå University in Sweden, and colleagues.

Seven months after starting on the drug, she was dead, the researchers wrote online in Neurology. Her physicians ruled out progressive multifocal leukoencephalopathy (PML), a known and frequently fatal side effect of natalizumab therapy.

Svenningsson and colleagues concluded that her death resulted from "rebound neuroinflammation as a result of the development of natalizumab anti-drug antibodies."

Noteworthy was that the patient had shown unusual reactions to the drug starting with the fourth infusion, including chills and fever, they suggested.

"We recommend that repeated moderate to severe infusion reactions in the beginning of natalizumab treatment should prompt the cessation of treatment and assessment for the development of natalizumab anti-drug antibodies," Svenningsson and colleagues wrote.

The patient was first diagnosed with MS in 2001 when she was 32. She was initially treated with interferon-beta-1a, but was switched to natalizumab in November 2007 when MRI scans showed growth in brain lesions. Because the scans did not show contrast enhancement, her doctors determined that her blood-brain barrier remained intact.

Natalizumab was given at the standard dose of 300 mg every 4 weeks by infusion.

The chills and fever that started with the fourth treatment became progressively more severe with subsequent infusions, the researchers indicated. After the sixth, she developed progressive gait abnormalities, ataxia, and significant mental deterioration.

MRI scans showed new hyperintense T2 lesions as well as multiple areas of contrast enhancement. Molecular tests of the patient's cerebrospinal fluid for the JC virus were negative, arguing against PML, which is caused by reactivation of latent JC virus infection.

At that point, she was transferred to a regional hospital. Her disability level progressed to 9 on the EDSS scale, compared with a level of 3 when she started on natalizumab. She was unable to get out of bed and was uncommunicative.

Another MRI scan showed additional contrast-enhancing lesion growth. Brain biopsy results were consistent with acute MS inflammation, Svenningsson and colleagues reported, "with infiltrating activated macrophages as well as signs of blood-brain barrier breakdown."

Most important, anti-natalizumab antibodies were found at a level of 335 mg/L, "among the highest recorded among anti-drug antibody positive patients identified in Sweden," the researchers indicated. The antibodies were predominantly of the IgG3 complement-fixing class.

The woman underwent plasmapheresis and her doctors wanted to perform an autologous stem cell transplant, but her condition was too poor for that, and she died in June 2008.

Autopsy findings showed no evidence of infectious pathogens in the central nervous system. The conclusion was that acute MS inflammation was the cause of her symptoms and eventual death.

Svenningsson and colleagues considered the possibility that the anti-natalizumab antibodies had triggered an anti-idiotype reaction, which could have led to an autoimmune attack on ligands of VLA-4, VCAM-1, and fibronectin. But in vitro studies using serum samples from the patient showed no signs of anti-idiotype reactivity.

Other clinicians have reported cases in which patients worsened while on natalizumab or who showed severe relapses after stopping the drug, Svenningsson and colleagues said, but their case was unusual in its fatal outcome.

__________________________

The study was funded by ALF, the KI Foundation, and the Swedish Association of Persons with Neurological Disabilities.

Study authors reported relationships with Biogen Idec, Bayer-Schering, Baxter Medical, Sanofi, and Merck Serono.

Source reference:

Svenningsson A, et al "Fatal neuroinflammation in a case of multiple sclerosis with anti-natalizumab antibodies" Neurology 2013.


The article can be seen here.
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PostPosted: Mon Mar 04, 2013 11:19 pm    Post subject: (Abst.) Anti-JC virus antibody prevalence in MS cohort Reply with quote

From Multiple Sclerosis Journal, March 4, 2013:

Quote:
Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort

Tomas Olsson1
Anat Achiron2
Lars Alfredsson3
Thomas Berger4
David Brassat5
Andrew Chan6
Giancarlo Comi7
Mefkure Eraksoy8
Harald Hegen4
Jan Hillert1
Poul Erik Hyldgaard Jensen9
Lucia Moiola7
Kjell-Morten Myhr10
Annette Oturai9
Sven Schippling11,12
Aksel Siva13
Per Soelberg Sorensen9
Anne-Kathrin Trampe6
Thomas Weber14
James Potts15
Tatiana Plavina15
Dominic Paes15
Meena Subramanyam15

1Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
2Multiple Sclerosis Center, Sackler School of Medicine, Tel Aviv University, Israel
3Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
4Clinical Department of Neurology, Innsbruck Medical University, Austria
5Department of Neurology, University of Toulouse, France
6Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
7Department of Neurology and Institute of Experimental Neurology, Vita-Salute San Raffaele University, Milan, Italy
8Department of Neurology, Istanbul University, Turkey
9Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Denmark
10Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
11Institute for Neuroimmunology and Clinical MS Research, University Hospital Hamburg-Eppendorf, Germany
12Department of Neuroimmunology and Clinical MS Research, University Medical Center Zurich, Switzerland
13Department of Neurology, Istanbul University, Turkey
14Neurologische Klinik, Marienkrankenhaus Hamburg, University of Hamburg, Germany
15Biogen Idec Inc., Weston, MA, USA
Tomas Olsson, Center for Molecular Medicine, L8:04, Karolinska Hospital (Solna), 171 77 Stockholm, Sweden. Email: tomas.olsson@ki.se

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study.

Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

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PostPosted: Mon Mar 25, 2013 4:44 pm    Post subject: (AAN) Disease course & outcome of 15 PML patients... Reply with quote

Presented at the annual AAN conference in San Diego, March 16-23, 2013:

Quote:
P01.168] Disease Course and Outcome of 15 Monocentrically Treated Natalizumab-Associated Progressive Multifocal Leukoencephalopathy (PML) Patients

Stefanie Dahlhaus, Bochum, NRW, Germany, Robert Hoepner, Bochum, NRW, Germany, Andrew Chan, Bochum, Germany, Ingo Kleiter, Bochum, Germany, Ortwin Adams, Duesseldorf, NRW, Germany, Alexandra Schroeder, Bochum, NRW, Germany, Kerstin Hellwig, Bochum, Germany, Ralf Gold, Bochum, Germany

OBJECTIVE:

To evaluate the clinical outcome of 15 patients with natalizumab-associated PML treated at a single MS reference center.

BACKGROUND:

Little is known about the functional outcome of natalizumab-associated PML patients. Also it is not evident, to which extent MS disease activity resumes when natalizumab was stopped after onset of PML.

DESIGN/METHODS:

The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardized treatment as described in Wenning NEJM 2009. Sequential CSF analyses for JCV-DNA were performed at the Institute for Virology, University Duesseldorf. EDSS and Karnofsky Score in the year pre-PML, at PML-diagnosis and post-PML.

RESULTS: The mean follow up time of the patients was 19.2 months. None of them died. 3 patients had a Karnofsky Score greater than 70, 10 patients between 50-70 and 2 patients 40 or lower. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at the latest examination.

CSF became virus-free in 9 of the 15 patients after a median time of 4 months. In 6 patients disease activity reappeared after a median time of 13.5 months from PML diagnosis. 7 patients received glatirameracetate, 1 patient interferon ß-1a and 2 had to be escalated to fingolimod. 5 patients were stable without continuous immunotherapy.

CONCLUSIONS: Although the clinical outcome of natalizumab-treated PML patients is much better than in HIV-associated PML-patients, this may be further improved by treatment at reference centers using standardized therapy regimens. Systematic studies of follow-up immunotherapies after MS-PML are critically needed.

Category - MS and Related Diseases: Clinical Science

Monday, March 18, 2013 2:00 PM

Session P01: Multiple Sclerosis: Treatment Safety
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PostPosted: Tue Apr 02, 2013 5:45 pm    Post subject: (AAN) Possible disability stabilization w/Tysabri Reply with quote

Presented at the AAN conference in San Diego, March 16-23, 2013:

Quote:
[S21.004] Decreased Microglial Activation Precedes Stabilization of Disability in Multiple Sclerosis Patients Treated with Natalizumab

Marios Politis, London, United Kingdom, Paolo Giannetti, London, United Kingdom, Flavia Niccolini, London, United Kingdom, Paul Su, London, United Kingdom, Federico Turkheimer, London, United Kingdom, Adam Waldman, London, United Kingdom, Richard Reynolds, London, United Kingdom, Richard Nicholas, London, United Kingdom, Paola Piccini, London, United Kingdom

OBJECTIVE:

To investigate in vivo whether one-year treatment with natalizumab can influence levels of activated microglia in brain areas which were found to be related to disability in Multiple Sclerosis (MS) patients.

BACKGROUND:

Our baseline data (Politis et al., 2012 Neurology) have demonstrated pathological increases of microglial activation in the cortex of MS patients and particularly in the precentral and postcentral gyrus that correlated with measures of clinical disability.

DESIGN/METHODS:

10 MS patients (8F; 8 relapsing and 2 secondary progressive; EDSS range: 3.5–6.5) received a second 11C-PK11195 PET scan (a marker of microglial activation) one-year following treatment with natalizumab and were followed up clinically (with EDSS) six months before the first PET scan to 18 months after the second PET scan (total of 36 months). We used optimized modeling and segmentation procedures for the quantification of 11C-PK11195 binding.

RESULTS:

The eight MS patients who completed the natalizumab infusions showed decreased 11C-PK11195 binding in the cortex (30%; p=0.0027), in the precentral (34%; p=0.0099) and postcentral (67%; p=0.0051) gyrus, following one-year treatment with natalizumab.

Two MS patients had intermittent infusions or withdrew from therapy. The MS patient with intermittent infusions showed milder decreases in 11C-PK11195 binding (∼18%) whereas the MS patient who withdrew from treatment had an average of 23% increases in 11C-PK11195 binding. The correlations between 11C-PK11195 binding in cortex, precentral and postcentral gyrus and EDSS scores observed at baseline were not present following one-year treatment with natalizumab (p>0.1). The progressive increase of EDSS scores before initiation of Tysabri (4.9% per six months) [was] slowed down 12 months following natalizumab until the end of the observation period with a borderline statistical EDSS improvement at 18 months (p=0.064).

CONCLUSIONS:

One-year treatment with natalizumab was associated with decreases of cortical microglial activation that could be relevant to the stabilization of physical disability.

Category - MS and Related Diseases: Clinical Science

Wednesday, March 20, 2013 2:45 PM

Session S21: Multiple Sclerosis: Novel Imaging and Pathology of Lesions
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PostPosted: Wed Apr 03, 2013 7:03 pm    Post subject: Low body weight linked to PML risk w/Tysabri in MS Reply with quote

From MedScape Today, April 3, 2013:

Quote:
Low Body Weight Linked to PML Risk With Natalizumab in MS

Susan Jeffrey

San Diego, California — An intriguing new study suggests that low body mass may be associated with an increased risk for developing progressive multifocal leukoencephalopathy (PML) in the setting of therapy with natalizumab (Tysabri, Biogen Idec) for multiple sclerosis (MS).

"Higher PML incidence definitely trends toward lower body weights," said John Foley, MD, a neurologist at Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, Utah.

There is about a 54% excess in PML cases in Europe Union compared with expected cases based on percentage of world-wide use, Dr. Foley pointed out. "The EU/US [European Union/United States] paradox may be at least partially explained actually by the fact that the demographics, at least when using Utah and Swedish controls as surrogates for the US and EU, are very, very different both in age and in weight of those on natalizumab," he told Medscape Medical News.

Natalizumab concentration clearly increases with time, he said, and in this study, high natalizumab concentrations appeared to occur particularly in patients with lower body weight. "High natalizumab saturations correlate best to populations with both low body weight and very high drug level per kilogram. Extended-dose therapy can decrease concentration and saturation as you might expect, and may well be a viable therapy for PML risk reduction."

The findings were presented here at the American Academy of Neurology (AAN) 65th Annual Meeting. The study was supported by Biogen Idec/Elan Pharmaceuticals.

Lower Weight, Higher Risk?

Natalizumab is an effective treatment for MS, but the risk for PML is an important issue, considering its use, the study abstract notes. Factors that have already been identified as predictors of PML susceptibility include duration of therapy and positivity for antibodies to the JC virus upon starting therapy.

The so-called EU/US paradox in PML cases has been described previously, he said. If cases were evenly distributed between these regions on the basis of use, there should be approximately 125 cases of PML in the EU. Instead, there have been 193 cases, a 54% excess over expected numbers, much of which has been ascribed previously to an increased use of immunosuppressants in the EU, he noted.

In this study, Dr. Foley looked at pharmacokinetic and pharmacodynamic effects of prolonging the interval between doses of natalizumab as a possible risk mitigation strategy against PML.

He collected demographic and clinical data from a cohort of 301 natalizumab-infusing patients at their clinic and compared their data with an aggregate of such patients worldwide, including a cohort of 38 patients with PML.

Looking at drug concentrations, results showed a tight correlation coefficient between drug saturation of VLA-4 lymphocytes and the concentration per kilogram, ranging from 85% mean saturation to 95% in those with the lowest weight. "This weight relationship was also recognized early on in the natalizumab experience, and actually is in the PI [prescribing information], that higher drug clearance was seen in patients with higher body weight," Dr. Foley noted.

The researchers then stratified saturation by both weight and concentration and found that most patients with saturations of 90% to 95% were in the lower weight category, but they also mapped into the higher concentration category. "When you look at what we called our 'ultra-saturators,' our 95%-plus saturators, here you start seeing stratification into this really high concentration and low-weight group."

On the basis of these findings, he said, "we hypothesized that if increased concentrations and saturations occur in low body weight populations, and are germane to PML risk, then we should see more PML cases in patients with lower body weight."

By collaborating with several other centers, they were able to collect data on 38 patients with PML (almost 12% of the reported cases associated with natalizumab treatment) to look at the weight distribution between EU and US populations. In this PML cohort, the median weight was 64 kg, with a mean of 70 kg across all patients, and no significant difference was seen between the European and US populations in weight distribution among PML cases.

However, at their institution in Salt Lake City, Dr. Foley noted, "our median weight is 78 kilos, 14 kg greater than the average PML case. And in keeping with the theory, we do see in the Swedish cohort, which we are using as a surrogate for the EU population, as being much closer to the PML cohort at 69 kg."

They then divided patients into weight "bins" to try and elucidate the relationship further. In their clinic, 13% of patients fell into the 60 kg or less bin, whereas in the Swedish population of 1127 natalizumab-treated patients, 22% fell into the 60 kg or less bin. "And what we see is there is a striking elevation in PML cases in that lowest-weight category, almost 3-fold different from the US and almost 2-fold different from the combined (EU and US) data," he said.

"The other question is then what happens when you do dose extension, and here we're dose extending from a standard 28 to 30 days, to a 6-week regimen," Dr. Foley concluded. They don't yet have a lot of patients receiving this 6-week regimen, but they saw a significant reduction in mean concentration with the 6-week dosing cycle; in addition, saturation dropped roughly 6.5% in this small cohort.

"In my way of thinking of this, I think you want to avoid these real high saturations for a long time," he said during the discussion.

"Fascinating" Observation

Asked for comment on these findings, Lily Jung Henson, MD, medical director of the Swedish Neuroscience Institute, Seattle, Washington, said she found this potential relationship between lower weight and higher PML risk very interesting.

"It's one of those observations where only time will tell but it's certainly really fascinating," she told Medscape Medical News. The question is, though, which came first, she points out; lower body weight may mean the patients are healthier, or it may mean they are more ill, and therefore more likely to get PML.

"So there are a lot of unknowns, but I think it's just fascinating," she concluded.


____________

The study was supported by Biogen Idec/Elan Pharmaceuticals. Dr. Foley reports having received personal compensation for activities with Biogen Idec, Teva Neuroscience, and Genzyme Corporation as a consultant and research support from Biogen Idec and Novartis. Dr. Jung Henson has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Genzyme Corporation, Novartis, and Pfizer Inc. One of her family members holds stock and/or stock options in Merck & Co Inc. She has received research support from Biogen Idec, Novartis, and Genzyme Corporation.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract S30.002. Presented March 20, 2013.

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PostPosted: Fri Apr 05, 2013 9:03 pm    Post subject: (Abst.) Tysabri may reduce fatigue in MS: TYNERGY trial Reply with quote

From PubMed, April 5, 2013:

Quote:

PLoS One. 2013;8(3):e58643.

Natalizumab Treatment Reduces Fatigue in Multiple Sclerosis. Results from the TYNERGY Trial; A Study in the Real-Life Setting

Svenningsson A, Falk E, Celius EG, Fuchs S, Schreiber K, Berkö S, Sun J, Penner IK, For The Tynergy Trial Investigators.

Dept of Pharmacology and Clinical Neuroscience, Umeå University and University Hospital of Northern Sweden, Umeå, Sweden.

Fatigue is a significant symptom in multiple sclerosis (MS) patients. First-generation disease modifying therapies (DMTs) are at best moderately effective [in improving] fatigue.

Observations from small cohorts have indicated that natalizumab, an antibody targeting VLA-4, may reduce MS-related fatigue. The TYNERGY study aimed to further evaluate the effects of natalizumab treatment on MS-related fatigue.

In this one-armed clinical trial including 195 MS patients, natalizumab was prescribed in a real-life setting, and a validated questionnaire, the Fatigue Scale for Motor and Cognitive functions (FSMC), was used both before and after 12 months of treatment to evaluate a possible change in the fatigue experienced by the patients.

In the treated cohort all measured variables, that is, fatigue score, quality of life, sleepiness, depression, cognition, and disability progression were improved from baseline (all p values<0.0001). Walking speed as measured by the six-minute walk-test also increased at month 12 (p = 0.0016). All patients were aware of the nature of the treatment agent, and of the study outcomes.

CONCLUSION:

Natalizumab, as used in a real-life setting, might improve MS-related fatigue based on the results from this one-armed uncontrolled study. Also other parameters related to patients' quality of life seemed to improve with natalizumab treatment.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00884481.

PMID:23555589
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PostPosted: Tue Apr 09, 2013 11:37 am    Post subject: (AAN) PML: Evolving risk-stratification paradigm Reply with quote

SEE ALSO THE APRIL 3 POST, ABOVE

Presented at the AAN conference in San Diego, March 16-23, 2013:

Quote:
[S30.002] Natalizumab-Related PML: An Evolving Risk-Stratification Paradigm

John Foley, Salt Lake City, UT

OBJECTIVE:

To further characterize natalizumab related PML risk factors and present the case for ameliorating risk via dosing interval prolongation.

BACKGROUND:

PML remains an important issue when considering natalizumab as an MS therapy. Our group has analyzed many demographic factors and potential biomarkers to reduce PML risk. We have identified patient body mass as a novel potential predictor of PML susceptibility. Dose interval extension has been suggested as a possible PML risk mitigation tactic. We present data providing insight on the pharmacokinetic/pharmacodynamic effects of dose extension.

DESIGN/METHODS:

Primary demographic and clinical data was collected in a cohort of 301 natalizumab-infusing patients at a single clinic. This data set was compared to an aggregate of natalizumab-infusing patients worldwide, including a cohort of natalizumab-related PML cases.

RESULTS:

Mean natalizumab plasma concentrations rose from approximately 16 to 32 ug/ml over the first two years of therapy. Patients with a body mass of <= 75 kg have higher mean natalizumab concentrations and VLA-4 lymphocyte saturations. Initial data analysis of 29 PML cases revealed a body mass of <= 75 kg in 83% and was statistically different from the single site comparative population (n=301). We will present additional PML cases, reference populations, and the relationship of natalizumab concentration to dosing interval extension.

CONCLUSIONS:

Patients with high natalizumab concentrations, resulting from a low body mass and/or natalizumab exposure duration, may be at a higher risk for PML. We hypothesize that high natalizumab plasma concentrations reduce immunosurveillance of the JC virus in the brain, allowing for the development of PML. Increasing the interval between natalizumab infusions may be an effective method for reducing plasma natalizumab concentrations and may decrease PML risk. Further research confirming this hypothesis is warranted.

_____________________

Supported by: Biogen, Idec., Elan Pharmaceuticals.
Category - MS and Related Diseases: Clinical Science

Wednesday, March 20, 2013 2:15 PM

Session S30: Multiple Sclerosis: Treatment Safety[url][/url]
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PostPosted: Fri Apr 26, 2013 9:13 am    Post subject: (Abst.) Disease course & outcome in 15 PML patients Reply with quote

It's rare to find some information about the Tysabri patients with PML, but here is some. From PubMed via NTK Institute, April 26, 2013:

Quote:
J Neurol Neurosurg Psychiatry. 2013 Apr 19.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients

Dahlhaus S, Hoepner R, Chan A, Kleiter I, Adams O, Lukas C, Hellwig K, Gold R.

Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, , Bochum, Germany.

OBJECTIVE:

Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre.

PATIENTS AND METHODS:

Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3-6 monthly intervals.

RESULTS:

The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50-70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis.

CONCLUSIONS:

Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

PMID:23606731
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PostPosted: Wed Jun 05, 2013 8:21 pm    Post subject: Tysabri screening test may be unreliable Reply with quote

From MedPage Today, June 5, 2013:

Quote:
Tysabri Screening Test May Be Unreliable

By John Gever, Deputy Managing Editor, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

About one-third of multiple sclerosis patients testing negative for antibodies against the JC virus -- suggesting that natalizumab (Tysabri) would be relatively safe -- were found to have active viremia, researchers said.

The report, published in the June 6 issue of the New England Journal of Medicine, raises the specter that patients with negative JC serology results could be given natalizumab when they may actually be at high risk for progressive multifocal leukoencephalopathy (PML), an often fatal type of brain inflammation.

PML is caused by JC virus becoming active in the brain. Natalizumab appears to contribute to reactivation of latent JC virus infections. MS patients with such infections face a PML risk while on natalizumab ranging from about 0.01% to 0.1% depending on the presence of other risk factors

Eugene O. Major, PhD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., and colleagues reported having tested blood samples from 49 patients for anti-JC virus antibodies and for JC virus DNA.

In 26 of the patients, the samples were obtained immediately before starting on natalizumab. Samples from the other 23 were obtained after at least 2 years of periodic natalizumab infusions.

Ten patients in the first group were found to have JC viral DNA in their blood, with four lacking a positive result in anti-JC virus antibody testing. (Seronegativity was defined as antibody titers of less than 2,560 units.)

In the group of 23 patients tested after 2 years of natalizumab treatment, seven were found to be viremic and two were seronegative, the researchers reported.

Overall, they indicated, six of 17 patients (35%) showing JC viremia were seronegative with the antibody test.

Fisher's exact test indicated that the rate of viremia in the 49 patients was significantly greater than in 18 healthy volunteers also undergoing viral DNA testing (P=0.003), in whom none showed evidence of the virus in blood.

"The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously," Major and colleagues wrote.

Currently, the FDA and natalizumab's label recommend JC virus antibody testing before the drug is started in MS patients. The risk of PML is believed to be virtually nil for patients without JC virus infection, but false-negative serological test results would lead to incorrect PML risk prediction.

"To establish risk-stratification algorithms for PML in patients who receive potent immunomodulatory therapies, a single measurement of viral activity, such as a test for antibodies to JC virus, may be useful but not sufficient to assess risk," the researchers wrote. They recommended "a more comprehensive risk-mitigation strategy" that involves periodic testing during natalizumab treatment.

Natalizumab's label now calls for repeat serology testing every 6 months, citing the risk of new JC virus infections that may occur during treatment. Infections are relatively common in the general population. In the current study, 12 of the 18 healthy volunteers were seropositive.

On the other hand, a positive test result is not an absolute contraindication to natalizumab. "The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors," it says. Such risk factors include duration of natalizumab therapy and prior history of immunosuppressant treatment.
_____________________________________

The study had no commercial funding.

One co-author reported relationships with Biogen Idec (maker of natalizumab), Teva, Genzyme, Abbott, Acorda, and Novartis. Other authors were NINDS employees and had no disclosures.

Primary source: New England Journal of Medicine

Source reference:
Major E, et al "JC Viremia in natalizumab-treated patients with multiple sclerosis" New Engl J Med 2013; 368: 2240-2241.
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PostPosted: Sun Jun 16, 2013 5:56 pm    Post subject: (Abst.) CNS herpes simplex & varicella-zoster virus... Reply with quote

From PubMed via NTK Watch, June 13, 2013:

Quote:
Clin Infect Dis. 2013 May 31.

Central Nervous System Herpes Simplex and Varicella-Zoster Virus Infections in Natalizumab-Treated Patients

Fine AJ, Sorbello A, Kortepeter C, Scarazzini L.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology.

We report 20 natalizumab-treated patients with multiple sclerosis who developed laboratory-confirmed central nervous system (CNS) herpesvirus infections. Aside from progressive multifocal leukoencephalopathy, other CNS opportunistic infections have been rarely reported during natalizumab treatment. We encourage heightened awareness due to the risk for serious outcomes.

PMID: 23728144
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PostPosted: Tue Aug 06, 2013 5:45 pm    Post subject: JC virus syndrome w/pure cerebellar degeneration Reply with quote

From the New England Journal of Medicine Journal Watch, August 6, 2013:

Quote:
August 5, 2013

Newly Recognized JC Virus Syndrome with Pure Cerebellar Degeneration

Robert T. Naismith, MD Reviewing Schippling S et al., Ann Neurol 2013 Jul 19;

A case of cerebellar granule cell neuronopathy with progressive ataxia and cerebellar atrophy in the setting of natalizumab treatment for multiple sclerosis

Progressive multifocal leukoencephalopathy is the protypical presentation of JC virus cerebral infection, and it is always associated with T2 lesions on magnetic resonance imaging (NEJM JW Neurol April 8 2013--[see below]). A cerebellar degeneration syndrome has been described in the setting of HIV that may be due to a genetic variation in the JC virus.

This case report describes a patient with multiple sclerosis (MS) who, after being treated with natalizumab for more than 4 years, developed progressive gait ataxia and appendicular signs over 4 months. MRI did not show any new T2 or gadolinium-enhancing lesions but did demonstrate cerebellar atrophy. Cerebrospinal fluid (CSF) was positive for JC virus by PCR testing, natalizumab was stopped, and plasma exchange promptly removed circulating natalizumab. The patient continued to worsen over 2 months, prompting a cerebellar biopsy establishing severe destruction of the granule cells in the cortical structure, with immunohistochemistry detecting JC virus within the nucleus of remaining granule cells.



This is the article and comment referred to above--from NEJM Journal Watch, April 8, 2013:
Quote:

Consensus Guidelines for Diagnosis of Progressive Multifocal Leukoencephalopathy

Robert T. Naismith, MD reviewing Berger JR et al. Neurology 2013 Apr 9.

An algorithmic approach advanced by the American Academy of Neurology Neuroinfectious Disease Section

Diagnosis of progressive multifocal leukoencephalopathy (PML) has become more challenging. Additional cases have been associated with monoclonal antibody therapy, sometimes in those with pre-existing neurological disease (e.g., multiple sclerosis). The American Academy of Neurology Neuroinfectious Disease Section has now created a consensus statement on PML diagnostic criteria.

PML diagnosis is based on a constellation of progressive neurological symptoms and signs, evidence of demyelination on magnetic resonance imaging, and corroboration with cerebrospinal fluid (CSF) testing. Symptoms most often include behavioral and cognitive abnormalities; other common symptoms are weakness, gait abnormalities, visual field deficits, speech and language disorders, and incoordination. PML spares the optic nerves and spinal cord. Other presentations are less common, but a high index of clinical suspicion for atypical presentations is warranted for those at increased risk.

Distinguishing PML from MS on neuroimaging is a challenge, especially early in the presentation. Gadolinium enhancement (typically a faint rim or speckled interior) can occur in an estimated 50% of patients with natalizumab-associated PML and 15% of those with HIV-associated PML. PML with HIV is characteristically multifocal, but with natalizumab-associated PML, it is often monofocal. Lesions of PML are most common in frontal and parietal lobes but can also occur in basal ganglia, external capsule, and posterior fossa. Whereas in MS, lesions are periventricular and small, PML lesions are more frequently >3cm, located in subcortical regions, and have minimal to mild mass effect. CSF cell counts are typically <20 cells/mm3 with a mildly elevated protein level. Ultrasensitive polymerase chain reaction testing for JC virus in CSF is >95% sensitive. When >200 copies of JC virus DNA are present per mL of CSF, most diagnostic labs can detect the virus. In non-HIV patients who develop PML because of a therapeutic immunosuppressant, JCV copy number may be low in early disease. The NIH laboratory can detect 10 copies/mL. If the suspicion for PML remains high with a negative CSF JC virus PCR, additional spinal fluid can be checked. Less commonly, brain biopsy is required for definitive diagnosis and to exclude other etiologies (e.g., CNS lymphoma).

COMMENT

Early diagnosis of PML remains critical, as symptom duration is related to prognosis. Luckily, we are now better informed about who is at greatest risk for PML based on serum JC virus antibody status (JW Neurol May 29 2012). Clinicians should educate patients taking anti-inflammatory therapies known to be associated with PML to contact the clinician for all new neurological symptoms. If PML is suspected, we should work up these patients according to this algorithm. Although the CSF JC virus PCR test is very good, it is not perfect. If a high clinical suspicion for PML remains and CSF testing is negative, continued testing, follow-up, and potentially a brain biopsy may be warranted.

CITATION(S):

Berger JR et al. PML diagnostic criteria: Consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013 Apr 9; 80:1430.
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PostPosted: Thu Sep 12, 2013 4:40 pm    Post subject: (Abst.) Risk factors ... PML & Tysabri Reply with quote

This abstract gives a succinct summary of the current situation with respect to the risk of PML in MS patients taking Tysabri.

From PubMed via NTK Institute, September 12, 2013:

Quote:
Neurology. 2013 Sep 3;81(10):858-9.

Risk factors for rare diseases can be risky to define: PML and natalizumab

Major EO, Douek DC.

From the Laboratory of Molecular Medicine and Neuroscience, NINDS (E.O.M.), and Human Immunology Section, Vaccine Research Center, NIAID (D.C.D.), NIH, Bethesda, MD.

When rare neurologic diseases become topics of editorials in journals such as Nature Neuroscience,(1) the New England Journal of Medicine,(2) and Neurology®,(3) there is usually something more of general interest than the rare disease itself. Such is the case for progressive multifocal leukoencephalopathy (PML), the JC virus-induced demyelinating disease that was once relegated for discussion to the back of the textbook, whether in microbiology or neurology. Not any longer. Incidence and publication of cases of PML have risen more than 50-fold within the last decade. Renewed recognition of PML started in the mid-1980s, when it was recognized as an AIDS-defining illness in 1%-3% of all HIV-1-infected persons, still true in the era of combined antiretroviral therapy.(4) PML is reported in patients with underlying neoplastic diseases, organ transplants, and rheumatic diseases, but by 2004, PML dramatically entered the mainstream as a serious adverse event associated with a promising monoclonal antibody therapy, natalizumab, for treatment of relapsing-remitting multiple sclerosis (MS). Nature itself showed that demyelinating diseases of substantially different etiologies and pathologies can occur in the same brain, and remarkably enough in some cases, not with a fatal outcome.

In 2006, the estimated occurrence of PML in natalizumab-treated patients with MS, with an average treatment of 17 months, was 1 per 1,000.(5) With more than 115,000 patients globally treated with natalizumab for longer periods of time, that estimate is 1 per 330.(6) In patients who test positive for antibodies to JCV, have a clinical history of immune suppressive treatment before natalizumab, and have received more than 24 doses, the number of PML cases is 1 per 90.

PMID: 23925759
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PostPosted: Sun Sep 29, 2013 6:27 pm    Post subject: (Abst.) JCV granule cell neuronopathy... Reply with quote

From PubMed via NTK Institute, September 25, 2013:

Quote:
Ann Neurol. 2013 Jul 19.

JCV granule cell neuronopathy and GCN-IRIS under natalizumab treatment

Schippling S, Kempf C, Büchele F, Jelcic I, Bozinov O, Bont A, Linnebank M, Sospedra M, Weller M, Budka H, Martin R.

Neuroimmunology and Multiple Sclerosis Research Section (nims), Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Progressive multifocal leukoencephalopathy (PML) is the most common clinical presentation of JC virus-associated CNS disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab.

Here we report clinical, radiological and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab.

GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under treatment with natalizumab, especially in cases where cerebellar atrophy can be visualized by MRI.


PMID: 23868420
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PostPosted: Sun Oct 06, 2013 4:01 pm    Post subject: (ECTRIMS) Survival predictors in Tysabri-related PML Reply with quote

Presented at the annual ECTRIMS conference in Copenhagen, October 2-5, 2013:

Quote:
MS and infections

Thursday, October 03, 2013, 15:45 - 17:00

Predictors of survival in natalizumab-associated progressive multifocal leukoencephalopathy


T. Dong-Si, A. Gangadharan, S. Gheuens, M. Wenten, J. Philip, J. McIninch, S. Datta, N. Richert, C. Bozic, G. Bloomgren, S. Richman (Weston, US)

Background:

Natalizumab is a highly effective therapy for relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy (PML). As of 6 May 2013, 359 PML cases in natalizumab-treated patients have been confirmed worldwide; however, the overall survival rate remains relatively high (77%).

Objectives:

To examine factors which predict improved survival in a large natalizumab-associated PML population.

Methods:

Differences in demographic and clinical characteristics for surviving vs non-surviving patients were assessed. Expanded Disability Status Scale (EDSS) score prior to PML diagnosis was evaluated to determine whether pre-existing disability affected survival. Kaplan-Meier analysis was used to model survival function. Data as of 3 October 2012 were used.

Results:

At the time of this analysis, 235 of 298 (79%) patients were alive and 63 (21%) patients were deceased. The mean follow-up time from PML diagnosis was 18.1 months for survivors; mean time from diagnosis to death was 3.8 months in non-survivors. As compared with non-survivors, surviving patients were significantly younger at diagnosis (mean 44.0 years vs 49.5 years, P<0.0001), had significantly lower EDSS scores prior to PML diagnosis (mean 3.6, median 3.5 vs mean 5.3, median 5.5; P=0.0004), and had a significantly lower cerebrospinal fluid JC viral load at the time of diagnosis (mean 106,382 copies/mL vs 575,552 copies/mL; P<0.0001). Time from symptom onset to diagnosis was similar in both groups. Patients with less extensive disease on MRI at diagnosis (eg, unilobar PML) had a higher survival rate than those with widespread disease (82% vs 72%). JC viral load at diagnosis was significantly lower in patients with unilobar disease compared with widespread disease (median 384 copies/mL vs median 694 copies/mL; P=0.0222). However, in non-survivors there was no difference in JC viral load between those with unilobar vs those with widespread disease (median 2903 copies/mL vs median 2076 copies/mL; P=0.3031).

Overall survival of the PML population was 82.1% at approximately 4 months, 81.0% at approximately 9 months, 75.8% at approximately 15 months, and 73.9% at approximately 29 months.

Conclusions:

In this analysis, younger age at diagnosis, less functional disability prior to diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis predicted improved survival in natalizumab-associated PML.

____________________

Supported by Biogen Idec Inc. All authors are employees of Biogen Idec.
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PostPosted: Wed Oct 16, 2013 11:24 am    Post subject: (Abst.) Brainstem PML lesion mimicking MS plaque... Reply with quote

From PubMed, October 16, 2013:

Quote:
Neurology. 2013 Oct 15;81(16):1470-1471.

Brainstem PML lesion mimicking MS plaque in a natalizumab-treated MS patient

Tortorella C, Direnzo V, D'Onghia M, Trojano M.

From the University of Bari, Italy.

A 47-year-old woman with relapsing-remitting multiple sclerosis (MS), treated with natalizumab for 14 months, reported dysphagia. Brain MRI demonstrated small fluid-attenuated inversion recovery-hyperintense T1-hypointense unenhancing lesions of the right pons and left medulla initially interpreted as new MS plaques ... but increased and became confluent over 3 months .... CSF demonstrated the presence of JC virus (4015 DNA copies).

PMID: 24127190


The abstract can be seen here.
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PostPosted: Fri Oct 25, 2013 1:45 pm    Post subject: (Abst.) Tysabri-induced PML [one case] Reply with quote

Sometimes people say they wish they knew how the Tysabri-related PML cases are doing. The data isn't readily available but here is a brief report on one case.

From PubMed, October 25, 2013:

Quote:
Clin Nucl Med. 2013 Oct 22.

Natalizumab-Induced Progressive Multifocal Leukoencephalopathy

Thaker AA, Schmitt SE, Pollard JR, Dubroff JG.

From the Department of *Radiology; and †Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA.

A 55-year-old woman with known relapsing-remitting multiple sclerosis (RRMS) on natalizumab (Tysabri®) for 3 years was admitted to the hospital with worsening word-finding difficulties and gait instability. Neurologic examination revealed right hemianopia, right arm hemiplegia, right-sided sensory loss, and global aphasia. The patient underwent MRI and PET imaging with concurrent electroencephalogram. She was subsequently diagnosed with natalizumab-induced progressive multifocal leukoencephalopathy (PML) and treated with plasmapheresis, intravenous immunoglobulin, and high-dose intravenous steroids. Steroids were continued over a 3-month hospital course and tapered upon discharge. Speech, arm strength, and ambulation have since improved.

PMID: 24152618


The abstract can be seen here.
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