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    ECTRIMS Summer School, Bari, Essential Lab Outcomes ECTRIMS Summer School, Bari, Essential Lab Outcomes Presentation Transcript

    • Phase IV study:Essential lab outcomesGavin GiovannoniBarts and The London School of Medicine and Dentistry
    • Why lab outcomes?• Diagnostic testing– Positive & negative predictive testing• Pathogenesis– Immunology– Aetiology– Disease progression & recovery– Disease heterogeneity• Pharmacovigilance• Monitor disease processes– Prognosis (high vs. low risk patients)– Monitoring effect of therapeutic interventions
    • Diagnostic & pathogenic markers
    • The evolving clinical definition of MS1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Reportby the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann NY Acad Sci 1965;122:552-68.2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.Ann Neurol 1983;13:227-31.3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines fromthe International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonaldCriteria". Ann Neurol 2005;58:840-6.5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonaldcriteria. Ann Neurol. 2011;69:292-302.
    • Will Rogers Phenomenon in Multiple Sclerosis1879 - 1935“When the Okies left Oklahoma and moved to California,they raised the average intelligence level in both states.”
    • Will Rogers Phenomenon in Multiple SclerosisSormani et al. Ann Neurol 2008;64:428–433.PoserMcDonald
    • Intrathecal synthesis of IgGImages courtesy of Alastair Compston and Ed Thompson.Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7.Carl Lange – Colloidal Gold CurveIsoelectric focusing with immunfixation
    • Diagnostic criteria for Primary Progressive MSPolman et al. Ann Neurol 2005;58:840-6.
    • Accumulation of disability in PPMS:stratified by intrathecal IgG abnormalitiesProportion Progressing as PercentEpoch CSF- CSF+6 mo 7.3 9.812 mo 15.0 20.418 mo 22.8 28.124 mo 25.4 34.3Years to Progression2.43 2.26Based on data from a second meeting of the DSMB and assume no therapeutic effect0 1 2 3Years0.00.20.40.60.81.0ProportionProgressingPositiveNegativeCSFSlide courtesy of Jerry WolinskyP =0.03
    • Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
    • What constitutes a useful diagnostic test or set of criteria?TARGET DISORDERPRESENT ABSENTDIAGNOSTICTEST RESULT+ a b a + b- c d c + da + c b + d a + b + c + dFrom these we determine the sensitivity and specificity as follows:SENSITIVITY = a/(a+c) > 80%SPECIFICITY = d/(b+d) > 80%Neurobiol Aging 1998; 19:109-116.
    • A clinico-pathoanatomical study of multiple sclerosis diagnosisSENSITIVITY = True+ve /(True+ve + False-ve)Eye Department, Hvidovre Hospital, Denmark.• Neuropathological examination of 518 consecutive patients withclinically definite MS revealed a correct diagnosis in 485 cases (94%).• Clinical diagnosis had been established by a neurologist in all cases.• Erroneous diagnosis included a variety of other neurologicaldisorders.• Also investigated was a randomly selected series of 33 patients with aclinical diagnosis of probable MS:– post mortem confirmation of MS was obtained in circa 66%.– The remainder the error pattern was similar to the above.Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
    • Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.PML complicating treatment with natalizumab and IFNb-1a for MS
    • A clinico-pathoanatomical study of multiple sclerosis diagnosisSPECIFICITY = True-ve /(True-ve + False+ve) ?~25% of cases of MS are undiagnosed in life (asymptomatic or benign cases)Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.
    • Other diagnoses - MRI white matter changes• ADEM• Ageing• Behcet’s syndrome• Cerebrovascular disease• Decompression sickness• Fat embolism• HIV encephalitis• HTLV1-associated myelopathy• Hydrocephalus• irradiation• Leukodystrophies• Migraine• Mitochondrial encephalopathy• MND• Neurosarcoidosis• Phenylketonuria• PML• SSPE• SLE/APL• TraumaMiller DH. (1997)
    • Lennon et al. Lancet 2004;364:2106-12.NMO
    • Pharmacovigilance markers
    • Take special care with Interferon-beta-1b:If you might have a disorder of the immune system in whichabnormal proteins are found in the blood (monoclonalgammopathy), you must check this with your doctor before youuse interferon beta-1b. Patients who have the rare conditionknown as monoclonal gammopathy may develop problemswith their small blood vessels (capillaries) leading to shock(collapse) which can be fatal, when they use medicines likeinterferon-beta-1b.See also 4. Possible side effects.
    • “There are known knowns; there are things we know that we know. There are knownunknowns; that is to say, there are things that we now know we dont know. But there arealso unknown unknowns – there are things we do not know we dont know.”United States Secretary of Defense, Donald Rumsfeld
    • Salzman C. N Engl J Med 1990 20; 323:827-9.
    • NatalizumabProgressive multifocal leukoencephalopathy (PML)Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.359 cases -30th April 201383 (23%) died276 (77%) aliveMild disability – 10%Moderate disability – 50%Severe disability – 40%5% NAbs – infusion reactions
    • Natalizumab PML risk stratification toolAnti-JC virus antibody statusNegative PositivePrior immunosuppressant useNatalizumab treatment>2 YearsNatalizumab treatment>2 YearsNo YesNo Yes No YesLowest HighestRelative PML Risk< 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887MitoxantroneAzathioprineMethotrexateCyclophosphamideMycophenolateCladribineRituximabEtc.
    • Neurology 2012;78(Suppl.): [S41.006]
    • Predicting autoimmunity following treatment of MS with alemtuzumab• 30% of alemtuzumab-treated ptsdevelop autoimmune side-effects(primarily thyroid disease andidiopathic thrombocytopenia)• Aim: To define predictive factors forautoimmune side-effects• Sera of 141 pts screened at baselinefor 8 different cytokines/chemokinesA combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients atlow risk of developing autoimmunity following treatment with alemtuzumabJones JL, et al. ECTRIMS 2011, Amsterdam. P1009Sensitivity NPV Specificity PPVIL-21 alone 81 84 70 66IL-7 alone 76 76 54 54CCL21 alone 63 65 49 47IL-21 or IL-7 98 97 41 55IL-21 OR IL-7OR CCL2198 91 12 45Given that pts may elect to receive treatment basedon results of this test – most weight given tominimizing false negative results. Combining IL-21and IL-7 into a single test offers improved testaccuracy over IL-21 alone. CCL21 did not improvetest accuracy010203040IL-7Autoimmunity No autoimmunity050010001500IL-211.0Sensitivity0.80.60.40.20.00.0 0.2 0.4 0.6 0.8 1.01.0Sensitivity0.80.60.40.20.00.0 0.2 0.4 0.6 0.8 1.01-SpecificityIL-21 and IL-7 levels in seraof pts who did or did notdevelop autoimmunityReceiver operatingcharacteristic (ROC) curves
    • Anti-natalizumab AntibodiesNumber of Patients at RiskPlaceboAntibody NegativeTransiently PositivePersistently Positive3155682037296550193228353818262645261625248506162424048716222294801522216470141920846014162004491415Weeks0.00.10.20.30.40.50 12 24 36 48 60 72 84 96 108 12029%Placebo17%Antibody Negative17%Transiently Antibody Positive34%Persistently Antibody PositiveCumulativeProportionofPatientswithSustainedDisabilityProgression(EDSS)*,†*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placeboNumber of Patients at RiskPlaceboAntibody NegativeTransiently PositivePersistently Positive3155682037296550193228353818262645261625248506162424048716222294801522216470141920846014162004491415Weeks0.00.10.20.30.40.50 12 24 36 48 60 72 84 96 108 12029%Placebo17%Antibody Negative17%Transiently Antibody Positive34%Persistently Antibody PositiveCumulativeProportionofPatientswithSustainedDisabilityProgression(EDSS)*,†*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo0.730.220.160.48*0.00.10.20.30.40.50.60.70.80.9AdjustedAnnualizedRelapseRate(95%CI)Placebo(n=315)Antibody Negative(n=568)TransientlyAntibody Positive( n=20)PersistentlyAntibody Positive(n=37)*p=0.009 vs. antibody-negative patients0.730.220.160.48*0.00.10.20.30.40.50.60.70.80.9AdjustedAnnualizedRelapseRate(95%CI)Placebo(n=315)Antibody Negative(n=568)TransientlyAntibody Positive( n=20)PersistentlyAntibody Positive(n=37)*p=0.009 vs. antibody-negative patientsCalabresi et al, Neurol 2007Impact of anti-natalizumab antibodies on . . . . .Annualized relapse rate Progressive disability
    • Natalizumab infusion reactions• Acute hypersensitivity reactions are well-recognized• Generalized urticaria, dizziness, fever, rash, rigors, pruritus,nausea, flushing, dyspnea, chest pain• Onset generally during or within 1 hour of second infusion• Incidence ~4%• severe anaphylactic/anaphylactoid reactions <1%• Most reactions are associated with anti-natalizumabantibodies• Treatment:• immediate and permanent cessation of natalizumab• antihistaminesRudick et al, NEJM 2006
    • Monitoring effect of therapeutic interventions
    • Reduced efficacy due to NAbs – systematic reviewFarrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
    • Clinical importance of neutralising antibodies against interferonbeta in patients with relapsing-remitting multiple sclerosisSorensen et al. Lancet 2003; 362: 1184–91.
    • Mean change in EDSSMalluci et al. Neurology 2004.
    • Predictive markers for response to interferontherapy in patients with multiple sclerosisMalucchi et al. Neurology 2008;70:1119–1127.
    • Jacob Elkins, James Sheridan, Lakshmi Amaravadi,Katherine Riester, Gilmore O’NeillNeurology 2012;78(Suppl.): S31.004
    • Prognostic markers
    • Scandinavian Simvastatin Survival Study (4S)Reprinted from The Lancet, Vol. 344, Scandinavian Simvastatin Survival Study Group, 1383-13890.950.900.850.80ProportionAliveYears Since Randomization0 1 2 3 4 5 6SimvastatinPlaceboLog rank: p=0.00030.001.00
    • Can body fluid biomarkers compete with MRI?
    • Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
    • Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.Spinal fluid neurofilament levels
    • Gunnarsson et al. Ann Neurol 2010; Epub.CSF NFL
    • Scientific Process
    • The Scientific Process of Biomarker DevelopmentPhase 0 – Assay Developmentsource of reagents, sensitive, specificreliable, reproduciblelow coefficients of variationquality controlHypothesis & study objectivesPhase 1 – Animal, in vitro modelscross-sectional “proof of concept” studiesTarget: population vs. patientsSingle vs. panel of biomarkersPatient groups vs. normalsPatient group vs. disease controlsPhase 2 – Longitudinal studyStudy patient characteristics – age, disease type, etc.Method of case selection – retrospective, prospective,stratification, matching (age, sex, etc.)Treatment received - randomisedPhase 3 – Independent longitudinal studiesMulti-centre studiesPhase 4 - FDA & EMEA licensingSurrogate end-pointBiobankingReportingPhase 3 – Longitudinal studyMulti-biomarker strategy – soluble biomarkers incorporatedwith imaging markers.Study duration – median follow-up timeClinical and data end-points definedData and statistical analysis – define models used, handlingof missing data, etc.InternalValidationExternalValidation
    • Body fluid biomarkers in clinical practice• Diagnostic• CSF OCBs• Baseline Risk• Serum protein electrophoresis• JCV serology• VZV serology• TB Screening• Monitoring• Bloods: FBC, LFTs, U&E, TFTs & beta-HCG• Urine (rbcs)• Serology• NABs IFN-beta• NABs Natalizumab• JCV serology• CSF• JCV DNA• NFL