Natalizumab v. Interferon Beta head to head study

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study; Lanzillo R, Quarantelli M, Bonavita S, Ventrella G, Lus G, Vacca G, Prinster A, Orefice G, Tedeschi G, Brescia Morra V; Acta Neurologica Scandinavica (Nov 2011)

Background -  No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). Aim -  To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS. Patients and methods -  We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI). Results -  In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a-treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). Conclusions -  After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes.

GLANCE trial

Goodman A et al.  GLANCE : Results of a phase 2 randomized double blind placebo controlled study.  Neurology 2009; 72:806-812.

Study adding Tysabri to glatiramer-- safety trial.  Results showed increased natalizumab antibodies, but safe otherwise.  Efficacy was much better in combination group than in the GA alone group re MRI.  110 patients were randomized, half got GA + placebo, others GA + NAT.  Took patients with active disease year before entry.

NABs and Steroids-- the Mayo Clinic critically appraised

Zarkou S., et al. I Dean Wingerchuk)  Ar corticosteroids efficacious for preventing or treating neutralizaing antibodies in multiple sclerosis patients treated with Beta interferons?  A Critically appraised topic. The Neurologist 2010; 16: 212-214.

Bottom line-- idea of using steroids in any scenario for Nabs is based on dubious evidence.

Outcomes among natalizumab patients acquiring PML

Vermesch P et al.  Clinical outcomes of natalizumab - associated progressive multifocal leukoencephalopathy.  Neurology 2011; 76:1696-1704

Authors analyzed 35 patients with PML related to natalizumab.  25 survived.  Survivors had lower age and EDSS on mean, and shorter time to diagnosis of PML.  86 % had unilobar or multilobar disease on initial PML brain MRI, whereas 70 percent of fatal cases has widespread disease on MRI.  Disability scores (Karnofsky scale) among survivors was highly variable.  16/36/48 % respectively had mild, moderate or severe disability.

Tidbits
Almost all patients withdrawn from natalizumab got IRIS and were treated with i-c corticosteroids, in addition to plasma pheresis to removed natalizumab.  They also received mirtazepine or mefloquine due to in vitro studies showing an effect on replication. 

Tables show much less nonfatal PML in US v. Europe.  Rate of nonfatal to fatal PML was, US: 3:8 in Europe 22:2.  This is not discussed but I wonder if more nonfatal PML slips through cracks in US  and is either not diagnosed or reported. 

Posterior fossa PML was rare.  Most patients had enhancing lesions.

Vitamin D and African Americans with MS

Gelfand JM, Cree BAC, McElroy J et al.  Vitamin D in African Americans with Multiple Sclerosis.  Neurology 2011; 76:1824-1830. 

339 African American MS patients and 342 controls were compared.  MS patients had lower vitamin D levels than controls, but the lower levels did not affect disease severity.  The differences were explained by geography and climate, as well as ancestry. 

Natural history of MS relapses

Bejaoui K, Rolak L.  What is the risk of permanent disability from an MS relapse?  Neurology  2010: 74: 900-902.

Authors review >2500 relapses and find only 7 with relapse with EDSS >6 that did not recover. 2 of those were on interferons at the time.  Two had a presentation of tumefactive MS.  They concluded that the fear of sudden irreversible disability should not affect treatment decisions. 

4 aminopyridine toxicity mimicking autoimmune limbic encephalitis

Neurology 72; 2009: 1100-1101

A 22 year old man ingested 30 tablets of 4-AP. He was agitated but oriented, flushed, mildly febrile, hypertensive.  EEG showed spikes and polyspikes and waves. CSF was normal.   MRI showed bitemporal hyperintensity on T2 imaging as well as affecting anterior cingulum.  Cardiac EF initially was 24 % but recovered.  He awoke to be mute and amnestic.  He recovered over one year but still had short term memory problems.   

differential diagnosis of long segment myelopathy suggesting NMO

Compression/ spondylitic myelopathy-- pearl- check enhancing scan for signet ring sign 

zoster myelitis-- history of shingles

paraneoplastic-- history of cancer

infective-helminth-- prior "Wells" syndrome, with eosiniphilia

cord AVM- history of worsening with Vasalva, singing, defecation, also check blood sensitive sequences and MRA cord

Sjogren's-- controversial, check CSF NMO as well as serum

B12 deficiency-- posterior cord

copper deficiency-- also posterior cord

stroke-- can affect almost any part of cord

multiple sclerosis/transverse myelitis-- check brain MRI

GBS/CIDP-- may be difficult to differentiate clinically, check nerve roots for radiculitis on MRI

CMV radiculitis -- in immunocompromised

Behcet's

betaseron pregnancy registry

www.betaseronpregnancyregistry.com

 

phone 800-478-7049

 

less than 100 people enrolled, 85 births

Pearls about natalizumab and PML

1.  PML appearance in natalizumab cases may include enhanced lesions and even ring enhancing lesions unlike HIV associated PML

 

2.  JC virus must be ordered as ultrasensitive assay as routine assay limit of sensitivity is around the fifty percentile of the (low) number of copies seen in some cases of Tysabri associated PML

 

3.  PML presentation can be any type of new neuro abnormality including aphasia, heimparesis, hemisensory loss and others.

 

4.  PML cases increase with Tysabri exposure up to two years but is not clear about more than two years.  Prior immunosuppressive therapy increases the risk of PML

 

5.  IRIS occurs after removal of natalizumab with sometimes precipitous decline in patient's status and even death.MRI usually shows GD+ enhancement, within 1-6 weeks after removing natalizumab.

 

6.  IRIS prevention is reason for using Solumedrol one gram iv per day for five days followed by long taper