Sunday, April 22, 2007

Interferon beta babies-- Pregnancy on MS treatment

Two articles and editorial. editorial by Waubant E and Sadovnick AD. Neurology 2005; 65:788-789. Articles in same issue editorialized are Sandberg-Wollheim M et al. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology 2005; 65:802-806. Boskovic R et al. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005; 65: 807-811.

DMT's (Disease modifying therapy) are abortifacient in monkeys, but not known to be so in humans. The first article showed that looking at the published literature cumulatively, patients on interferon do not have trouble getting pregnant. Pregnancy outcomes, defined by pregnancy loss and congenital malformations, were not different compared to placebo. The rate of miscarriage was at the upper limit of normal expected range. The numbers are reassuring and similar to those derived from glatiramer acetate. The women studied may not be representative since they were on clinical trials.

The Boscovic article compares people with MS who conceived on interferon DMT, who conceived after stopping interferons and healthy controls. There was a slight increased risk of miscarriage (spontaneous abortion) and smaller birth weight babies in those conceived while on DMT. There also was a suggestion that the rate of malformation might be higher.

The editorialist writes that "prudence suggests the discontinuation of IFN-1A and any DMT prior to initiating pregnancy whould remain the rule whenever possible."

Saturday, April 21, 2007

JC Virus/PML in MS

Khalili K et al. Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 2007;68: 985-990.
This review article of basic science issues is informative about the process of JC virus activation and infection with PML in MS patients. IN order for PML to occur, latent JC virus in kidney or lymphatic system must be activated, and disseminated to the CNS where destructive replication occurs in oligodendrocytes. Pathologically, patients with PML have the triad of demyelination, giant bizarre astrocytes and nuclear inclusions. It continues to occur in HIV patients despite HAART therapy (up to 5 % of patients prior to advent of HAART). It also is reported in leukemia, lymphoma, organ transplantation patients, after treatment of solid tumors, autoimmune disease, granulomatous disorders, agammaglobulinemia, or rarely without an associated disorder. More recently, two patients with MS and one with Crohn's d had exposure to natalizumab/other drugs and another to rituximab. HIV accounts for 80 % of cases.

JC virusAB is seen in 80 % of normals. PCR in urine is seen in 30 % of normals. Quantitative PCR (Q-PCR) can be measured in urine, serum, CSF and biopsy samples. Standardization issues and threshold issues are important. This also has been shown in the related condition, polyoma asociated nephropathy (PVN) in which screening the urine has been important. The authors hypothesize that screening the blood of patients may lessen the risk of PML. JC virus is occassionally seen in CSF of patients with MS. It is unknown if they are at risk of developing PML.

Targets for treatment include nucleoside analogues (cytarabine, cidofavir) cytokines, enzyme inhibitors, and JCV receptor blockers such as 5H2a chlorpromazine, mirtazepine, heparin, Tat inhibitors.

The authors note "Screening blood for JC viremia did not prove useful in the two MS cases and could provide a false level of security." "More MRI screening is needed."

Thursday, April 12, 2007

Contraindications of tizanidine (Zanaflex)

based on updated safety printout of Acorda Therapeutics. Beware of other CYP1A2 inhibitors that can cause toxicity. Beware of Ciprofloxacin, , fluvoxamine, other fluoroquinolones, antiarrythmics (amiodarone, mexiletine, propafenone, verapamil) cimetidine, famotidine, oral contraceptives, acyclovir, ticlodipine. The combinations can lead to potentiated sedative and hypotensive effects. tylenol used concomitantly delays t max by about twenty minutes.

Sunday, April 08, 2007

AAN position conclusions on Nabs

Treatment of MS with IFNß (Avonex, Betaseron, or Rebif) is associated with the production of NAbs to the IFNß molecule (Level A).
It is probable that the presence of NAbs, especially in persistently high titers, is associated with a reduction in the radiographic and clinical effectiveness of IFNß treatment (Level B).
It is probable that the rate of NAb production is less with IFNß-1a treatment compared to IFNß-1b treatment (Level B). However, because of the variability of the prevalence data, and because NAbs disappear in the majority of patients even with continued treatment (especially in those with low-titer NAbs), the magnitude and persistence of any difference in seroprevalence between these forms of IFNß is difficult to determine.
It is probable that the seroprevalence of NAbs to IFNß is affected by one or more of the following: its formulation, dose, route of administration, or frequency of administration (Level B). Regardless of the explanation, it seems clear that IFNß-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNß preparations (either IFNß-1a or IFNß-1b) given multiple times per week subcutaneously (Level A). Because NAbs may disappear in many patients with continued therapy, the persistence of this difference is difficult to determine (Level B).
Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) has been associated with a reduction in the therapeutic effects of IFNß on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, and which cutoff titer to apply (Level U).

Thursday, April 05, 2007

Tysabri Notes

Based on a teleconference witrh Carlo Tornatore, MD (Georgetown). He has experience with many patients with Tysabri and MS and has NIH research experience working with PML.
1. All patients have JC virus in their bone marrow. However, JC virus in the blood is abnormal and suggests an immunosuppressed state. (Test PCR either Athena or Mayo can be done at Quest labs). Patients with a negative JC virus may be eligible for Tysabri if they meet other criteria.
2. JC virus in blood along with MRI is repeated every six months. If postive, Tysabri is stopped. CSF can be checked and there "are no false positives in the CSF." If the PCR is positve they have PML. Generally CSF is checked if there is any question about a new lesion being PML.
3. PML (unlike NMO) does not affect optic nerves or spinal cord. Hypothesizes the oligodendrocytes are different.
4. Different cocktails for treating PML have been tried. Ara C is too toxic but a combination of alpha interferon, and sodafavir? is OK. The main thing is to stop the tysabri to reconstitute the immune system. To do so fully, he also phereses for 5 days followed by IVIG for five days.
5. He has 3 exacerbations in over 100 patients each treated for ?18 months. He used steroids for exacerbations.
6. Pretreat claritin and tylenol
7. jc virus pcr in blood helps if positive not if negative
8. take off tysabri if new lesions or if antibody positive
9. discounts rebound except after short term use
10. clinical trials good data both for newly diagnosed as well as breaking through
11. Work coming off on MR metrics, spectro, atrophy, vision
12. 9 % develop nabs but only 6 % have persistent ab's if persistent then stop drug (usually test after 6 months). Won't check again unless a clinical problem. Usually develop early. Athena or Focus labs. If someone is doing well with ab's.???
13. risk benefit is good in scenario of breakthrough disease
14. takes off platform therapy drugs for one month, 3 mo for other imm supp drugs prior to starting tysabri. Pulse steroids not a problem.
15. slightly increased infusion reactions in patients previously treated. NABs unknown