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."
Sunday, April 22, 2007
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."
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).
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
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
Thursday, March 29, 2007
High dose copaxone
Randomized, double blind dose comparison study of glatiramer acetate in relapsing-remitting MS . Cohen JA et al. Neurology 2007; 68:939-944. The study screened treatment naive patients EDSS 1-5, one relapse in prior year, about 45 patients in each group. Compared 20 v 40 mg. Trend towards less relapses in higher dose group. More injection reactions in higher dose group. MRI scores showed a trend favoring the higher dose group.
Friday, March 23, 2007
predictors of disability in MS
Langer-Gould A, Popat RA, Huang SM, Cobb K, et al. Clinical and demographic predictors of long-term disability inpatients with relapsing remitting multiple sclerosis. A systematic review. Arch Neurol 63: 1686-91 2006
Study based on meta-analysis, including studies in the literature since 1966 that met preselected criteria, including differentiation of RRMS, enrollment of greater than 40 patients, observation > 5 years, and followup collection exceeding 80 percent.
The most important predictors were sphincter symptoms at onset and early disease course outcomes. Age at onset, sex, were weak factors.
Study based on meta-analysis, including studies in the literature since 1966 that met preselected criteria, including differentiation of RRMS, enrollment of greater than 40 patients, observation > 5 years, and followup collection exceeding 80 percent.
The most important predictors were sphincter symptoms at onset and early disease course outcomes. Age at onset, sex, were weak factors.
High dose cytoxan for multiple sclerosis
Gladstone DE et al. High dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 2006; 63:1388-1393.
The authors studied refractory MS, defined as EDSS scores of 3.5 or higher after 2 or more FDA approved DMD's. 12 patients received 200 mg/kg over four days. No patients increased EDSS by more than one point. Five decreased by one or more points. Patients reported improvement in ll QOL measures.
Goal of therapy is to stop disease progression.
Procedure was 200 mg/kg based on IBW over f days. Hemorrhagic cystitis prevention was done with mesna and forced diruresis. Antibacterial, antiviral and antifungal prophylaxis was given. Evaluation included EDSS, neuro-opthalmologic evaluation and MRI and QOL eval using short form 36.
Patients suffered absolute neutropenia for nine days, received a median of i unit prbc's
Alternatives: mitoxantrone, stem cell mobilization (filgastrim)
The authors studied refractory MS, defined as EDSS scores of 3.5 or higher after 2 or more FDA approved DMD's. 12 patients received 200 mg/kg over four days. No patients increased EDSS by more than one point. Five decreased by one or more points. Patients reported improvement in ll QOL measures.
Goal of therapy is to stop disease progression.
Procedure was 200 mg/kg based on IBW over f days. Hemorrhagic cystitis prevention was done with mesna and forced diruresis. Antibacterial, antiviral and antifungal prophylaxis was given. Evaluation included EDSS, neuro-opthalmologic evaluation and MRI and QOL eval using short form 36.
Patients suffered absolute neutropenia for nine days, received a median of i unit prbc's
Alternatives: mitoxantrone, stem cell mobilization (filgastrim)
Thursday, February 15, 2007
Tysabri risk and possible interventions
Stuve O et al. Potential risk of PML with natalizumab therapy. Arch Neurol 2007; 64:169-176. Neurological Review. The authors point out that neurologists must be aware of possible therapies because the n of patients studied is likely to be low. Possible treatments include antivirals, immunomodulatory treatments, hematopoietic growth factors, plasma exchange, IVIG, leukopheresis and autotransfusion of leukocytes. Points of note: 1) the risk of developing PML among 3116 patients treated in studies was 0.1 % and the risk of PML among patients treated longer is not known. 2) JC virus is ubiquitous in all people in kidney, peripheral blood cells and normal brain at autopsy. The prevalence of antibodies is around 90 %. 3) The biological half life of natalizumab is around six months , far exceeding its pharmacological half life. Goals of a possible therapy: 1)eliminate JCV; 2) generate new competent WBC's with unbound VLA-4; 3)neutralize free natalizumab, and 4)eliminate free natalizumab. 1)Antivirals help PML in HIV patients. Reconstitution of CD4 and CD* lymphocytes maybe required to ensure a positive outcome in the patients. 2) Natlizumab is present in blood for 3-8 weeks after dosing. Elimination depends upon the interaction with VLA 4 which is reversible bond and follows normal thermodynamic rules. The idea is to change the binding strength and the in vivo binding equilibrium between natalizumab and VLA4. Existing interventions: cytarabine iv and it did not help HIV patients with PML. Cidofovir showed no benefit in one study. Drugs can cause renal failure and myelosuppression. Interferon alpha and beta and IL2 have case reports of improvement. No data exist of their efficacy. Serotonin 2 alpha blockers may prevent JC viral infection of oligodendrocytes. These drugs include olanzepine, ziprasidone, and risperidone. Hematopoeitic growth factors: pros: Theoretically IL7, G CSF, GM-CSF is well tolerated and might produce unbound lymphocytes. In theory it could be used with IVIG or plasma exchange. Cons: see article
Mitoxantrone for Devic's disease
Weinstock-Guttman B et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica. Arch Neurol 2006;63:957-963 The authors studied five patients over two years and felt they improved on MRI, edss.
Monday, February 12, 2007
Familial effects of the clinical course of MS
Hensieck AE et al. Neurology 2007; 68:376-383. There is concordance among family members for age at onset, NOT for severity. There are no apparent transmission patterns nor evidence for genetic loading. However, familial factors do affect the probability of an eventual progressive course (either PPMS or after RRMS, SPMS).
Saturday, February 03, 2007
Normal appearing white matter (NAWM)& disability
Vrenken H. Altered diffusion tensor in multiple sclerosis normal-appearing brain tissue: cortical diffusion changes seem related to clinical deterioration. Journal of Magnetic Resonance Imaging 2006; 23:628-636.
Prospective controlled study of normal looking white and gray matter. 64 MS patients and 20 healthy controls. The 64 MS patients had 38 RRMS, 14 SPMS, and 12 with PPMS. Whole brain diffusion coefficient (ADC maps) and fractional anisotropy (FA) were obtained. In NAWM, global FA was decreased and global ADC increased in MS patients v. controls. The changes in ADC in NAWM correlated with disability more strongly than T2 lesion load. In gray matter regional analysis, changes in both ADC and FA were significant.
Note the correlation with disability was still "modest at best"
Prospective controlled study of normal looking white and gray matter. 64 MS patients and 20 healthy controls. The 64 MS patients had 38 RRMS, 14 SPMS, and 12 with PPMS. Whole brain diffusion coefficient (ADC maps) and fractional anisotropy (FA) were obtained. In NAWM, global FA was decreased and global ADC increased in MS patients v. controls. The changes in ADC in NAWM correlated with disability more strongly than T2 lesion load. In gray matter regional analysis, changes in both ADC and FA were significant.
Note the correlation with disability was still "modest at best"
Copaxone and neuroprotection
Kahn O. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Multiple Sclerosis 2005; 11:646-651.
Two year study partly blinded with MR spectroscopy in treatment naive MS patients and controls. GA (Copaxone) reduced NAA, a surrogate of axonal injury. 18 patients who started GA were assessed, and four controls (subjects who elected not to begin therapy). The NAA/Cr increased in both groups. In the VOI (volume of interest) over two years, and the NAWM (normal appearing white matterO it increased by 10.7 and 7.1 in the treated group, and DECREASED by 8.9 and 8.2 % in the respective control groups.
Fred Lublin comments that while the number of patients is small, the study is ongoing (four more years) but warns that the attempts to correlate surrogate MRI markers for clinical disability have been "continually disappointing." Lublin wants to see proof that the marker NAA in MRS correlates with clinical measures, and also with other MRI measures such as balck holes and atrophy.
Two year study partly blinded with MR spectroscopy in treatment naive MS patients and controls. GA (Copaxone) reduced NAA, a surrogate of axonal injury. 18 patients who started GA were assessed, and four controls (subjects who elected not to begin therapy). The NAA/Cr increased in both groups. In the VOI (volume of interest) over two years, and the NAWM (normal appearing white matterO it increased by 10.7 and 7.1 in the treated group, and DECREASED by 8.9 and 8.2 % in the respective control groups.
Fred Lublin comments that while the number of patients is small, the study is ongoing (four more years) but warns that the attempts to correlate surrogate MRI markers for clinical disability have been "continually disappointing." Lublin wants to see proof that the marker NAA in MRS correlates with clinical measures, and also with other MRI measures such as balck holes and atrophy.
Wednesday, January 31, 2007
extension trials in MS-- Noseworthy
Extension trials-- limited benefit Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorialcomments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 200632 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7. Relapse rate was about .61 per patient per year in treated patients.
Monday, January 29, 2007
Antimeylin Antibodies and progression to MS
462 patients with CIS and at least 2 clinically silent lesions had anti MOG and anti MBP IgG and IgM antibodies measured with Western blot, and were followed for 24 months. There was no association found between the antibodies being present and the development of CDMS
Saturday, November 11, 2006
CHAMPS CHAMPIONS AND ETOMS
CHAMPS 383 patients with very recent (27 days) CIS involving the optic nerve. Patients had to have 2 or more clinically silent lesions at least 3 mm in diameter, one ovoid or periventricular. Conversion to CDMS was a new event lasting at least 48 hours or deterioration of at least 1.5 points on the EDSS. All patients got three day Solumedrol pulse with taper at onset of study. Study was terminated after a positive interim analysis. Mean followup was 31 months. With interferon B1a (Avonex) the likelihood of developing MS was reduced 44 % (p<0.002). Posthoc analysis looked at high and low risk groups. The probability of CDMS in patients getting placebo was 50 %, 64 % in a high risk group (n=40) and 46 % in non high risk group (n=150). High risk was defined as nine or more lesions on T2 or one or more Gadolinium enhancing lesions. Only 20 % of Avonex group had CDMS at two years. Avonex reduced CDMS by 63 % at year 2, and 66 % by year 3. NTT=6.7 to prevent one patient from developing CDMS. Critiques: questionable blinding by treating physicians who followed side effects of patients. Disability and relapse rate were not applicable as points of study. No information is given on brain atrophy. AE's-- flu like reaction was 54 %, depression 20 % (v. 26, and 13 % respectively). Patients withdrawn from study did not get f/u scans. Chance of getting CDMS or dropping out was 64 % in placebo group, 51 % in active group. Class I study, category A.
The extension trial open label CHAMPIONS the original patients were all given Avonex (early and delayed treatment groups). N of the groups was 100, 103 , respectively. Thus slightly more than half the patients entered CHAMPIONS and they were treated UP TO five years (ie. not all made it that long). In the 2 groups, the respective rate of CDMS was 36 and 48 %. The rate of CDMS was decreased by 35 % in the immediate treatment group (looking at numbers could be 25 %). The NTT was 8 to treat early to prevent CDMS at five years. The mean number of relapses over five years was .9 and 1.7, respectively. The median number of T2 lesions was 3.5 and 6.0 respectively.
ETOMS studied Rebif in patients with unifocal or multifocal neurologic syndromes. Patients had at least 4 lesions on T2, or 3 if one was incfratentorial or enhancing. The primary measure was conversion to CDMS. Initial steroids were not given uniformly. Entry was allowed up to three months post event, and polysymptomatic patients were included. 39 % were in fact multifocal. The primary endpoint was conversion to CDMS. Like CHAMPS, effect of treating physician blinidng was criticized. There were 309 patients, 154 in each group and one patient thrown out). In the Rebif group, 34 % converted to CDMS and in the placebo group, 45 % converted at two years. The benefit was about 25 %, with NTT at 9.1 to prevent one CDMS at 2 years. The relapse rates were .33 and .43, respectively. The median number of active T2 lesions was 2 and 3, respectively.Actual data, percent, for placebo and rebif group, respectively: proportion converting to CDMS 45, 34; mean annual relapse rate: .43, .33 {Note: this is much lower than in pivotal betaseron trial}; median EDSS change to year 2: 0,0; median SNRS baseline to year 2: 0,0; median active T2 lesions per scan: 3,2; median enhancing lesions per scan: 0, 0.5; median change in T2 lesion volume from baseline to year 2: 8.8; -13.0. Class I study, Category A.
The extension trial open label CHAMPIONS the original patients were all given Avonex (early and delayed treatment groups). N of the groups was 100, 103 , respectively. Thus slightly more than half the patients entered CHAMPIONS and they were treated UP TO five years (ie. not all made it that long). In the 2 groups, the respective rate of CDMS was 36 and 48 %. The rate of CDMS was decreased by 35 % in the immediate treatment group (looking at numbers could be 25 %). The NTT was 8 to treat early to prevent CDMS at five years. The mean number of relapses over five years was .9 and 1.7, respectively. The median number of T2 lesions was 3.5 and 6.0 respectively.
ETOMS studied Rebif in patients with unifocal or multifocal neurologic syndromes. Patients had at least 4 lesions on T2, or 3 if one was incfratentorial or enhancing. The primary measure was conversion to CDMS. Initial steroids were not given uniformly. Entry was allowed up to three months post event, and polysymptomatic patients were included. 39 % were in fact multifocal. The primary endpoint was conversion to CDMS. Like CHAMPS, effect of treating physician blinidng was criticized. There were 309 patients, 154 in each group and one patient thrown out). In the Rebif group, 34 % converted to CDMS and in the placebo group, 45 % converted at two years. The benefit was about 25 %, with NTT at 9.1 to prevent one CDMS at 2 years. The relapse rates were .33 and .43, respectively. The median number of active T2 lesions was 2 and 3, respectively.Actual data, percent, for placebo and rebif group, respectively: proportion converting to CDMS 45, 34; mean annual relapse rate: .43, .33 {Note: this is much lower than in pivotal betaseron trial}; median EDSS change to year 2: 0,0; median SNRS baseline to year 2: 0,0; median active T2 lesions per scan: 3,2; median enhancing lesions per scan: 0, 0.5; median change in T2 lesion volume from baseline to year 2: 8.8; -13.0. Class I study, Category A.
Meta-analysis favors glatiramer
Carra A. P635 ECTRIMS 2004. Odds ratio for relapse, disability progression favors glatiramer over interferon groups.
Based on pooled data of four open nonrandomized trials. Patients n= 695 with 135 patients on GA having less relapses and accumulated disability.
Based on pooled data of four open nonrandomized trials. Patients n= 695 with 135 patients on GA having less relapses and accumulated disability.
"Inflammation is Good"
On the horizon: possible neuroprotective role for glatiramer acetate. Kreitman RR and Blanchette F. Multiple sclerosis 2004. 10: S81-S89.
This non peer reviewed Teva sponsored article reviews evidence that disability in MS is caused by axonal damage, not inflammation, and that autoimmune T cells may protect against neuronal damage.
Paper has a nice discussion with lots of experts but no new data presented
This non peer reviewed Teva sponsored article reviews evidence that disability in MS is caused by axonal damage, not inflammation, and that autoimmune T cells may protect against neuronal damage.
Paper has a nice discussion with lots of experts but no new data presented
PRISMS-4
PRISMS-4: Long-term efficacy of interferon B1a in relapsing MS. The PRISMS Study Group Neurology 2001:56:1628-1636
Have 2 years double blind and another 2 years of dose blind assessment.Placeo patients at end of frist two years were rerandmoized to rebif 22 or rebif 44
90% of patients continued to PRISMS 4 . Relapse rate, time to first relapse, time to progression of disability all favored high dose rebif and initial treatment wih high dose rebif. High dose was associated with 29% fewer 1 point edss changes over 4 years compared to crossover. Time to EDSS progression was not significant in low dose rebif in ITT analysis.
Lab changes (liver, CBC) were also more common in high dose group .
Burden of disease increased in years 3 and 4 for high dose group.
Have 2 years double blind and another 2 years of dose blind assessment.Placeo patients at end of frist two years were rerandmoized to rebif 22 or rebif 44
90% of patients continued to PRISMS 4 . Relapse rate, time to first relapse, time to progression of disability all favored high dose rebif and initial treatment wih high dose rebif. High dose was associated with 29% fewer 1 point edss changes over 4 years compared to crossover. Time to EDSS progression was not significant in low dose rebif in ITT analysis.
Lab changes (liver, CBC) were also more common in high dose group .
Burden of disease increased in years 3 and 4 for high dose group.
multiple sclerosis compare interferons
Etemadifar M et al. Comparison of Betaferon, Avonex and Rebif in treatment of relapsing-remitting multiple sclerosis Acta Neurol Scand 2006 1113:283-287
Head to head trial single blind randomized trial of rrms patients with active disease (>2 relapses in 2 years) and EDSS < 5. 90 patients. Design was to see which agent is best to prevent progression of MS.
High dose agents were better than avonex on number of patients who were relapse free for two years (B 43 %, R 56% A 20%). EDSS declined more with high dose than with Avonex. However, looking at table 3, all three groups had mean EDSS under 2.
Conclusion in the paper that high dose is better is contradicted by the clinical effect size, as all three drugs had low EDSS at conclusion of the trial.
Head to head trial single blind randomized trial of rrms patients with active disease (>2 relapses in 2 years) and EDSS < 5. 90 patients. Design was to see which agent is best to prevent progression of MS.
High dose agents were better than avonex on number of patients who were relapse free for two years (B 43 %, R 56% A 20%). EDSS declined more with high dose than with Avonex. However, looking at table 3, all three groups had mean EDSS under 2.
Conclusion in the paper that high dose is better is contradicted by the clinical effect size, as all three drugs had low EDSS at conclusion of the trial.
Lit review by Doug Goodin/Coyle
http://www.medscape.com/viewprogram/6005
this CME program goes over evidence based medicine, treatment of CIS, and disease nonresponders in slide based format with either audio or transcript of lecture
this CME program goes over evidence based medicine, treatment of CIS, and disease nonresponders in slide based format with either audio or transcript of lecture
Friday, October 20, 2006
Trials of extension trials PRISMS
neurology practice guidelines: "Extension trials-- limited benefit
Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorial
comments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 2006
32 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.
Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7.
Relapse rate was about .61 per patient per year in treated patients."
Noseworthy JH How much can we learn from long-term extension trials in multiple sclerosis? Neurology 2006; 67: 930-931 editorial
comments on Kappos et al. Long term interferon beta 1a therapy in patients with relapsing MSNeurology 67: 944-953 2006
32 % patients randomized in PRISMS did not participate in the extension. Blinding was eliminated. Visits were in some cases conducted every two years or retrospecive evaluations were substituted. About 25 % patients entering extension did not remain on treatment. Brain atrophy was not reduced. The NTT (number to treat) early v 24 months later to prevent one point progression on EDSS was 27. Conclusion of safety is warranted, not that of efficacy.
Kappos et al-- 382 patients followed 8 years. 19 % progressed to spms. NABS generally disappeared with treatment. The authors claim 44 dose worked better than 22. 396/560 patients had EDSS < 3 at baseline; of those, 27 % went to EDSS of 4, 20 % went to an EDSS of six, 12 % to 6.5, and 6 % to edss of 7.
Relapse rate was about .61 per patient per year in treated patients."
Monday, September 25, 2006
Cytoxan for refractory MS high dose
Gladstone et al. High dose cyclophosphamide for moderate to severe refractory multiple sclerosis.Arch Neurol 63:10: 1388-1397
Patient selection: EDSS > 3.5 after 2 or more DMD's tried
Methods: 200/mg/kg cyclophosphamide over four days
Outcome measures : MRI neuroopthy exams every six months, EDSS quarterly, QOL measure every two years
Results: 12 patients followed median 16 months none increased EDSS more than 1 point. 5 decreased. Improvements were seen in QOL measure and MRI
Fine points
Mesna, forced diuresis to prevent hemorhhagic cystitis. Antibacterial, antifungal, anti viral prophylaxis used. Patients had median age 41, had disease median 15 years, 7 had tried mitoxantrone. 7/13 had spms. risk of hem cystitis is 2 percent, of transient dilated cardiomyopathy is 1 percent.. Fever, sepsis, zoster were common.
Note medline "Gladstone " for cyclophosphamide in MS CIDP MG
Patient selection: EDSS > 3.5 after 2 or more DMD's tried
Methods: 200/mg/kg cyclophosphamide over four days
Outcome measures : MRI neuroopthy exams every six months, EDSS quarterly, QOL measure every two years
Results: 12 patients followed median 16 months none increased EDSS more than 1 point. 5 decreased. Improvements were seen in QOL measure and MRI
Fine points
Mesna, forced diuresis to prevent hemorhhagic cystitis. Antibacterial, antifungal, anti viral prophylaxis used. Patients had median age 41, had disease median 15 years, 7 had tried mitoxantrone. 7/13 had spms. risk of hem cystitis is 2 percent, of transient dilated cardiomyopathy is 1 percent.. Fever, sepsis, zoster were common.
Note medline "Gladstone " for cyclophosphamide in MS CIDP MG
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