Top Seminars Neurofilaments & other Biomarkers
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Top Seminars Neurofilaments & other Biomarkers Top Seminars Neurofilaments & other Biomarkers Presentation Transcript

  • Role of neurofilaments & other biomarkers in blood and CSF Gavin Giovannoni Barts and The London
  • Why MS biomarkers? • 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 MS 1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y 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 from the 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 "McDonald Criteria". Ann Neurol 2005;58:840-6. 5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
  • Will Rogers Phenomenon in Multiple Sclerosis 1879 - 1935 “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
  • Will Rogers Phenomenon in Multiple Sclerosis Sormani et al. Ann Neurol 2008;64:428–433. Poser McDonald
  • Inactive CIS Active CIS RRMS MS diagnosed according the old Poser Criteria Inactive CIS Less active RRMS More Active RRMS MS diagnosed according the New McDonald Criteria
  • Intrathecal synthesis of IgG Images courtesy of Alastair Compston and Ed Thompson. Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve Isoelectric focusing with immunfixation
  • Diagnostic criteria for Primary Progressive MS Polman et al. Ann Neurol 2005;58:840-6.
  • Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities Proportion Progressing as Percent Epoch CSF- CSF+ 6 mo 7.3 9.8 12 mo 15.0 20.4 18 mo 22.8 28.1 24 mo 25.4 34.3 Years to Progression 2.43 2.26 Based on data from a second meeting of the DSMB and assume no therapeutic effect Slide courtesy of Jerry Wolinsky 0 1 2 3 Years 0.0 0.2 0.4 0.6 0.8 1.0 ProportionProgressing Positive Negative CSF P =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 DISORDER PRESENT ABSENT DIAGNOSTIC TEST RESULT + a b a + b - c d c + d a + c b + d a + b + c + d From 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 diagnosis SENSITIVITY = True+ve /(True+ve + False-ve) Eye Department, Hvidovre Hospital, Denmark. • Neuropathological examination of 518 consecutive patients with clinically 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 neurological disorders. • Also investigated was a randomly selected series of 33 patients with a clinical 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.
  • Lennon et al. Lancet 2004;364:2106-12. NMO
  • 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
  • Pathogenic markers
  • “Inflammation” “Oligodendrocyte Toxicity & Demyelination” Axonal Toxicity (conduction block) Axonal & Neuronal Loss Gliosis Remyelination & Axonal Recovery “Inflammation” Central Adaptation & Plasticity Key pathological processes in MS
  • Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology Magliozzi et al. Brain 2007; 130:1089-1104.
  • Increased urinary free immunoglobulin light chain excretion in MS
  • 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
  • -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822 Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004 P=0.002 Miller DH et al. Neurology 2007;68:1390-1401. Natalizumab and brain atrophy Mean (SE) percentage change in BPF
  • Very low risk age place of residence outdoor activity / sun exposure / sun screen diet / vitamin D supplements age of exposure to EBV smoking At risk High Risk Low risk RIS CIS MS family history genetics sex month of birth place of birth Unfavourable disease-modifying factorsdynamic risk factorsstatic risk factors dynamic protective factorsstatic protective factors MRI / evoked potentials changes Peripheral immunological changes T-regs (), NK cells, CD8 () Clinical disease In utero childhood Adolescence / early adulthood adulthood 1. Declining Physiology – “peripheral immunological endophenotype” 2. Biological disease threshold – “CNS endophenotype” 3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 4. Clinical disease a. Clinically isolated syndrome (CIS) b. Relapsing MS c. Relapsing secondary progressive MS d. Non-relapsing secondary progressive MS Favourable disease-modifying factors protective HLA haplotypes CNS changes (OCBs and microscopic pathology) 2 3 24b 24c 24d 24a 1 The MS ‘Endophenotype’
  • Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol. 2014 Mar;71(3):306-14.
  • Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol. 2014 Mar;71(3):306-14.
  • Vitamin D as an early predictor of MS activity and progression Ascherio JAMA Neurol. 2014 Mar;71(3):306-14.
  • P=0.007 Multivariate International CIS risk factor study - 25-OH D3 Conversion to CDMS] HR 95% CI P value 25-OH D3 0.996 0.993-0.999 0.01 P=0.008 Median Survival: 935 days vs. 1262 days Kuhle et al. submitted 2014.
  • Higher 25-OH vD is associated with lower relapse risk Simpson et al. Ann Neurol. 2010;68:193–203.
  • vD status predicts new brain MRI activity in MS Mowry et al. ANN NEUROL 2012;72:234–240. • EPIC is a 5-year longitudinal MS cohort study at the UCSF. • 469 subjects annual clinical evaluations, brain MRI, and biomarkers. • Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI = -0.091 to -0.003; p = 0.037).
  • Chicken or Egg Causation? Association?
  • The effect of the systemic inflammatory response on plasma vitamin 25 (OH) D concentrations adjusted for albumin Ghashut et al. PLoS One. 2014 Mar 25;9(3):e92614. Vitamin D3 CRP Albumin
  • Hypothesis “Hypovitaminosis D3 is a consumptive vitaminopathy.” Therefore, the association between low vD levels and disease is due to reverse causation. Causation? Association?
  • Immunomodulatory effects of vD in MS Correale et al. Brain 2009: 132; 1146–1160. Vitamin D3 Immune response
  • Seasonal Effects
  • Seasonal patterns in optic neuritis and MS: a meta-analysis Jin et al. J Neurol Sci 2000:181;56–64.
  • Seasonal prevalence of MS disease activity Meier et al. Neurology 2010;75:799–806.
  • vD and disease activity in MS before and during IFN-beta treatment Løken-Amsrud et al. Neurology. 2012 Jul 17;79(3):267-73.
  • Treatment effects
  • The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler. 2013 Oct;19(12):1571-9.
  • The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler. 2013 Oct;19(12):1571-9.
  • Pharmacovigilance markers
  • What is the diagnosis?
  • Take special care with Interferon-beta-1b: If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use interferon beta-1b. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like interferon-beta-1b. See also 4. Possible side effects.
  • ?
  • Natalizumab Progressive multifocal leukoencephalopathy (PML) Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74. 207 cases -1st February 2012 44 (21%) died 163 (79%) alive Mild disability – 10% Moderate disability – 50% Severe disability – 40% 5% NAbs – infusion reactions
  • Natalizumab PML risk stratification tool Anti-JC virus antibody status Negative Positive Prior immunosuppressant use Natalizumab treatment >2 Years Natalizumab treatment >2 Years No Yes No Yes No Yes Lowest Highest Relative PML Risk < 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887 Mitoxantrone Azathioprine Methotrexate Cyclophosphamide Mycophenolate Cladribine Rituximab Etc.
  • PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012) and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. Anti-JCV antibody index values may differentiate PML risk for those with no prior immunosuppression Index 1−24 months ≤0.9 0.1 (0, 0.41) ≤1.1 0.1 (0, 0.34) ≤1.3 0.1 (0.01, 0.39) ≤1.5 0.1 (0.03, 0.42) >1.5 1.0 (0.64, 1.41) 63 PML risk estimates (95% CI) per 1000 patients with no prior IS use Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228. 63 25−48 months 49−72 months 0.3 (0.04, 1.13) 0.4 (0.01, 2.15) 0.7 (0.21, 1.53) 0.7 (0.08, 2.34) 1.0 (0.48, 1.98) 1.2 (0.31, 2.94) 1.2 (0.64, 2.15) 1.3 (0.41, 2.96) 8.1 (6.64, 9.80) 8.5 (6.22, 11.38)
  • Predicting autoimmunity following treatment of MS with alemtuzumab • 30% of alemtuzumab-treated pts develop autoimmune side-effects (primarily thyroid disease and idiopathic thrombocytopenia) • Aim: To define predictive factors for autoimmune side-effects • Sera of 141 pts screened at baseline for 8 different cytokines/chemokines A combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients at low risk of developing autoimmunity following treatment with alemtuzumab Jones JL, et al. ECTRIMS 2011, Amsterdam. P1009 Sensitivity NPV Specificity PPV IL-21 alone 81 84 70 66 IL-7 alone 76 76 54 54 CCL21 alone 63 65 49 47 IL-21 or IL-7 98 97 41 55 IL-21 OR IL-7 OR CCL21 98 91 12 45 Given that pts may elect to receive treatment based on results of this test – most weight given to minimizing false negative results. Combining IL-21 and IL-7 into a single test offers improved test accuracy over IL-21 alone. CCL21 did not improve test accuracy 0 10 20 30 40 IL-7 Autoimmunity No autoimmunity 0 500 1000 1500 IL-21 1.0 Sensitivity 0.8 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1.0 Sensitivity 0.8 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity IL-21 and IL-7 levels in sera of pts who did or did not develop autoimmunity Receiver operating characteristic (ROC) curves
  • Neurology 2012;78(Suppl.): [S41.006]
  • Anti-natalizumab Antibodies Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients Calabresi et al, Neurol 2007 Impact 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-natalizumab antibodies • Treatment: • immediate and permanent cessation of natalizumab • antihistamines Rudick et al, NEJM 2006
  • Monitoring effect of therapeutic interventions
  • Reduced efficacy due to NAbs – systematic review Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
  • Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis Sorensen et al. Lancet 2003; 362: 1184–91.
  • Jacob Elkins, James Sheridan, Lakshmi Amaravadi, Katherine Riester, Gilmore O’Neill Neurology 2012;78(Suppl.): S31.004
  • Prognostic markers
  • Intrathecal synthesis of IgG Images courtesy of Alastair Compston and Ed Thompson. Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve Isoelectric focusing with immunfixation
  • Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  • Conclusion • Diagnostic/prognostic biomarkers • Intrathecal OCBs • IgG Index • Pharmacovigilance • Baseline screening • Monoclonal gammaopathy (IFNbeta) • Serology – VZV, JCV (immunosuppression) • Monitoring • FBC, LFTs, U&E, TFTs • Monthly platelets and possibly urine (alemtuzmab) • Serology – JCV (natalizumab) • CD56-bright cells (daclizumab) • NABs (IFNbeta and natalizumab) • Potential surrogate treatment markers • CSF neurofilament levels • Potential future baseline response markers • Type 1 interferon signature • PBMC transcriptomic profiles
  • Acknowledgements • Giovannoni • Sharmilee Gnanapavan • David Baker • Gareth Pryce • Sarah Al-Izki • Sam Jackson • Katie Lidster • Yuti Chernajovsky • Alex Annenkov • Anne Rigby • Michelle Sclanders • Larry Steinman • Peggy Ho • Charles ffrench-Constant • Robin Franklin • Siddharthan Chandran • David Hampton • Ian Duncan • Sam Jackson • Peter Calabresi • Avi Nath • Raj Kapoor • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS • Co-investigators • NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial