Disease modifying therapy in multiple sclerosis interferons

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  • Typical flu like symptoms can be treated with fever reducers.
  • Controlled High Risk Avonex Multiple Sclerosis Prevention Study In Ongoing Neurological Survelillance 13 47 83
  • Disease modifying therapy in multiple sclerosis interferons

    1. 1. DISEASE MODIFYING THERAPY IN MULTIPLE SCLEROSIS - INTERFERONS Prof. A.V. SRINIVASANEMERITUS PROFESSOR - THE TAMILNADU DR.M.G.R. MEDICAL UNIVERSITY 04-04-10
    2. 2. LAND MARKS IN MS: Top Ten Events...Thus Far 1868: MS described by Jean-Martin Charcot. 1878: Myelin discovered by Louis Ranvier. 1916: Detailed microscopic description made by James Dawson revealed the basic damage done in MS. 1935: An animal form of NIS (EAE) developed by Thomas Rivers, ultimately suggesting an autoimmune basis for the disease. 1946: National Multiple Sclerosis Society founded by Sylvia Lawry.
    3. 3.  1948: Under an early NMSS grant, oligoclonal bands discovered in the spinal fluid by Elvin Kabat and others, provided a diagnostic test suggestive of MS and linking MS to immune system problems. 1965: Definite criteria for MS diagnosis developed by NMSS expert committee. 1969-1970: ACTH used to treat MS exacerbations. This was the first controlled trial of a successful treatment for MS: it used newly standardized diagnostic criteria and rating scales to evaluate the efficacy of treatment. Success is a prize to be won. Action is the road to it. Chance is what may lurk in the shadows at the road side. - O. Henry
    4. 4.  1981: MRI first used to examine a person with MS. MRI revolutionized diagnosis and provided evidence that MS is a constantly active disease even when symptoms abate. 1993: Beta-interferon 1b (Betaseron) approved as the first drug to alter the course of MS. 2001:Macdonald’s criteria. Discipline Weighs Ounces Regret Weighs Tons
    5. 5. MS IN INDIA: 1.33/100000 – Singhal etal. 2.54% of total neurology admissions between January93 to March98 -Syal,Khandelwal N, PGI Chandigarh. In the Parsi - a prevalence of 26/100,000 – Wadia etal. Optico spinal form more common than west -Pandit et al. Class II HLA association in 23 MS - non Parsi origin DRB1*1501 (50%) similar to western studies.11 Resistance drains energy Acceptance saves it Cheerfulness sustains it -- Anonymous
    6. 6. LUCCHINETTI CATEGORISATION: Type 1- demyelination and macrophages relate products. Type 2-presence of immunoglobulin and complement. Type 3-lacks immunoglobulin and complement,early loss of myelin associate glycoprotein-oligodendrocyte dysfunction. Type 4-apoptosis of oligodendrocytes-DNA fragmentation. Every discovery contains an irrational element or 4 creative intuition
    7. 7. Favorable indicators: Early age of onset. Female sex. Optic neuritis as presenting episode. Sensory symptoms as presenting episode. Acute onset. Little residual disabilty. Long inter exacerbation period. Small lesion load.
    8. 8. Unfavorable indicators: Later age of onset. Progressive course. Male sex. Frequent exacerbations. Poor recovery. Involvement of cerebellar and or motor functions. More disease load in MRI. Positive oligoclonal bands.
    9. 9. New Queensquare’s criteria In 2007, new criteria were proposed in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal- cord) and DIT requires a new T2 lesion on a follow-up scan “ Back pain – prize human beings pay for their UPRIGHT POSTURE”
    10. 10. Three Categories of Treatment Treatment of disease activity. Treatment of exacerbations. Treatment of symptoms. A open foe may prove a curse ; but a pretended friend is worse
    11. 11. Rationale for disease modifying treatments in MS Relapsing remitting Secondary & primary MS progressive MSPrevent new inflammatory Prevent loss of nerve fibres:lesions: (neuroprotection)β-interferon ?lamotrigineCopaxone ?cannabinoidsMitoxantronePrevent development of Remyelination:secondary progressive MS: ?stem cells?possible with existingtreatments
    12. 12. Interferons : Discovered in 1957 Significant antiviral agents phenomenon where oneinfection with one virus interfereswith a subsequent infection withanother virus The Truth is fear and immorality are two of the greatest inhibitors of Performance too progress
    13. 13. What are they??A protein substance naturally produced in thebody and believed to function to modulate theimmune system. Interferons interact withreceptors on non-infected cells to promote thesynthesis of antiviral proteins that preventfurther infection. They belong to Cytokines,which are hormones of the immune system.
    14. 14. Beta InterferonBeta interferon-1a  Avonex – administered weekly by an intramuscularly injection (2003)  Rebif – administered subcutaneously three times a week (2002)Beta interferon-1b  Betaseron – administered subcutaneously every other day (1993)
    15. 15.  Early and aggressive treatment with immune stimulating interferons can delay diseae progression. Prevents crippling symptoms of MS “ Men of Genius Admired: Men of Wealth envied:women of power feared: But only women of character are trusted” -A- Friedman
    16. 16. Common Side Effects…  Typical Flu-like symptoms  headache, nausea, and fever  muscle aches Chills Irritation at the injection siteAlcohol and exposure to sunlight may irritate side effects
    17. 17. TRIALS:CHAMPIONS: Avonex altered long-term course MS in patientswho began treatment immediately after initial attack35% decrease in the rate of developing second attack42% reduction in new or enlarging T2 hyper intense lesions Avonex associated with fewer neutralizing antibodies. Binding antibodies decrease the medications efficacy. They hasten the drugs removal from the bloodstream. 10 0 80 Avonex 60 40 Rebif 20 Betaseron 0
    18. 18. June 18th 2003EVIDENCE: Showed that patients on Avonex who converted toRebif showed signs of relapse reduction  Patients taking Rebif had fewer active lesions per MRI scan for all studied activity July 21st 2003QUASIMS: Higher doses and frequencies of interferon beta arenot necessarily better with comparable disease progression  Annual Relapse rates Avonex - .52 Rebif - .69
    19. 19. Treatment of Underlying Disease Interferons vs. Glatiramer AcetateGlatirmer acetate is a substitute antigen that mimics myelinbasic protein. It inhibits the CNS immune reactions that areresponsible for tissue damage. Given subcutaneously daily injection Reduces number of attacks and brain lesions seen on MRI patients No flu-like side effects associated with interferons
    20. 20. Other trials: AFFIRM STUDY- NATALIZUMAB MONOTHERAPY MORE EFFECTIVE THAN INTERFERONS IN TREATING RRMS. BEYOND TRIAL-DOUBLE DOSE INTERFERON BETA1B – NO ADVANTAGE OVER CONEVENTIONAL DOSAGE. REGARD TRIAL - THRICE WEEKLY INTERFERON SHOWED NO ADVANTAGE OVER GLATIRMER ACETATE. ETOMS TRIAL- EARLY TREATMENT WITH INTERFERONS REDUCED SECOND ATTACK BY 24%
    21. 21. COMBINATION THERAPY: NATALIZUMAB WITH IM BETA 1A OVER INTERFERON AND PLACEBO – FORMER WAS BETTER – REDUCED MRI LOAD AND RELAPSES (RUDICK ETAL 2006) PML WAS A DREADED SIDE EFFECT IN TWO PATIENTS. COMBINATION OF MINOCYCLINE AND GLATIRMER ACETATE IS UNDER WAY NOW. BETA1A COMBINATION WITH GA (TULLMAN AND LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3 TRIAL IS ONGOING – RESULTS EXPECTED IN 2011 “ Maintaining the right attitude is easier than regaining the right mental attitude”
    22. 22. WHOM TO START AND WHEN TO TREAT: When to start DMD- as early as possible. Interferons,glatirmer acetate- RRMS. IFN beta – relapsing form of SPMS (goodin etal 2002). MITOXONTRONE - Relaping MS (RR,SP,PROG.RELAPSIN G). NO SUCCESFUL TRIALS FOR PPMS.
    23. 23. UNANSWERED QUESTIONS: DOSE vs DOSING FREQUENCY. DOES TIME ON THERAPY MATTER. WHEN TO START NATALIZUMAB. HIGH DOSE IFN vs NATALIZUMAB. “ Peace Rules the day where reason Rules the mind” - Colling
    24. 24. CONCLUSIONS: SIGNIFICANT ADVANCES HAVE BEEN MADE,IN IMMUNOPATHOLOGY,CATEGORISATION OF SEVERITY,DISEASE MODIFYING DRUGS AND THEIR USAGE. CRIPPLING DISABLTY CAN BE LIMITED,EARLIER DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY ARE AVAILABLE NOW. RESEARCH IS STILL ON IN FINDING THE ELUSIVE GENE OR AN ENVIRONMENTAL AGENT OR BOTH. DESPITE ALL THESE ADVANCES TWO THINGS ARE STILL UNANSWERED – CURATIVE THERAPY & THE EXACT CAUSE FOR MS. OVER 140 YEARS MS REMAINS AN UNSOLVED PUZZLE AND AN ENIGMA.
    25. 25. Take home advances in MS: Queen square criteria – Earlier diagnosis of MS. DIS & DIT – Predicts conversion rate to Definite MS even in CIS. NMO & NMO spectrum disorder – distinct disorder from MS? In terms of Biological difference thin line separates PPMS & SPMS.
    26. 26.  TH 17 a Subset of CD4 and Treg cells(expressing CD25 & transcription factor Fox p 3) – pro inflammatory – a significant advance in immunopathogenesis. Two new gene loci IL2 and IL 7 - IDENTIFIED – needs substantiation. EBV, SMOKING – INCREASES RISK OF MS WHILE Vitamin D – Decreases risk of MS.
    27. 27.  Negative prognosticators are, bladder symtoms as presentation, incomplete recovery from an attack, shorter interval between first and second attack and early accumulation of disability. Benign MS – percentage of cases less – they eventually progress – not ACTUALLY BENIGN.
    28. 28.  A MAGIC PILL – BASED ON PHRMACOGENETICS(DNA LEVEL) AND PHRAMACOGENOMICS(RNA LEVEL)OF AN INDIVIDUAL. PROTEOMICS INFACT RESEARCH BEYOND RNA LEVEL – FUTURE HOLDS PROMISE .
    29. 29. Dedicated to my familyfor making everything worthwhile
    30. 30. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOU

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