Your SlideShare is downloading. ×
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Update in body fluid markers giovannoni 25 jan 2013
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Update in body fluid markers giovannoni 25 jan 2013

888

Published on

Neuroimmunology meeting in Porto, Jan 2013

Neuroimmunology meeting in Porto, Jan 2013

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
888
On Slideshare
0
From Embeds
0
Number of Embeds
9
Actions
Shares
0
Downloads
20
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. Update in body fluid markers Gavin Giovannoni Barts and The London School of Medicine and Dentistry
  • 2. 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
  • 3. Diagnostic & pathogenic markers
  • 4. The evolving clinical definition of MS1. 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.
  • 5. 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.”
  • 6. Will Rogers Phenomenon in Multiple Sclerosis Poser McDonald Sormani et al. Ann Neurol 2008;64:428–433.
  • 7. Intrathecal synthesis of IgGCarl Lange – Colloidal Gold Curve Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Isoelectric focusing with immunfixation Images courtesy of Alastair Compston and Ed Thompson.
  • 8. Diagnostic criteria for Primary Progressive MS Polman et al. Ann Neurol 2005;58:840-6.
  • 9. Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities 1.0 P =0.03 Proportion Progressing as PercentProportion Progressing 0.8 Epoch CSF- CSF+ 6 mo 7.3 9.8 0.6 12 mo 15.0 20.4 18 mo 22.8 28.1 0.4 CSF 24 mo 25.4 34.3 Negative Years to Progression 0.2 Positive 2.43 2.26 0.0 0 1 2 3 Years Based on data from a second meeting of the DSMB and assume no therapeutic effect Slide courtesy of Jerry Wolinsky
  • 10. CSF oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude Dobson et al. JNNP; in press.
  • 11. Pharmacovigilance markers
  • 12. 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.
  • 13. Natalizumab Progressive multifocal leukoencephalopathy (PML) 312 cases -5th December 2012 69 (22%) died 243 (78%) alive Mild disability – 10% Moderate disability – 50% Severe disability – 40% 5% NAbs – infusion reactionsKleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
  • 14. Natalizumab PML risk stratification tool Anti-JCV Antibody Status MitoxantroneNegative Positive Azathioprine Methotrexate Prior Immunosuppressant Cyclophosphamide Use Mycophenolate Cladribine Rituximab No Yes Etc. Natalizumab Treatment Natalizumab Treatment >2 Years >2 Years No Yes No Yes Lowest1 in 14,285 Highest 1 in 1,666 1 in 192 1 in 555 1 in 94 Relative PML Risk Lowest Highest
  • 15. Neurology 2012;78(Suppl.): [S41.006]
  • 16. Predicting autoimmunity following treatment of MS with alemtuzumab • 30% of alemtuzumab-treated pts IL-21 and IL-7 levels in sera Receiver operating develop autoimmune side-effects of pts who did or did not characteristic (ROC) curves develop autoimmunity (primarily thyroid disease and 1500 1.0 idiopathic thrombocytopenia) 0.8 Sensitivity • Aim: To define predictive factors for 1000 0.6 IL-21 autoimmune side-effects 500 0.4 • Sera of 141 pts screened at baseline 0.2 for 8 different cytokines/chemokines 0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity NPV Specificity PPV 40 1.0IL-21 alone 81 84 70 66 0.8 SensitivityIL-7 alone 76 76 54 54 30 0.6 IL-7CCL21 alone 63 65 49 47 20 0.4IL-21 or IL-7 98 97 41 55 10 0.2IL-21 OR IL-7 98 91 12 45 0.0OR CCL21 0 Autoimmunity No autoimmunity 0.0 0.2 0.4 0.6 0.8 1.0Given that pts may elect to receive treatment basedon results of this test – most weight given to 1-Specificityminimizing false negative results. Combining IL-21and IL-7 into a single test offers improved testaccuracy over IL-21 alone. CCL21 did not improvetest accuracy 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
  • 17. Anti-natalizumab Antibodies Impact of anti-natalizumab antibodies on . . . . . Annualized relapse rate Progressive disabilityAdjusted Annualized Relapse Rate (95% CI) 0.9 0.5 Placebo Cumulative Proportion of Patients 0.8 Antibody Negative 0.73 0.4 Transiently Antibody Positive with Sustained Disability 0.7 ,† 34%* Progression (EDSS) Persistently Antibody Positive 0.6 0.48* 0.3 29% 0.5 0.4 0.2 17% 0.3 0.22 17% 0.2 0.16 0.1 0.1 0.0 Placebo Antibody Negative Transiently Persistently 0.0 (n=315) (n=568) Antibody Positive Antibody Positive ( n=20) (n=37) 0 12 24 36 48 60 72 84 96 108 120 *p=0.009 vs. antibody-negative patients Weeks Number of Patients at Risk Placebo 315 296 283 264 248 240 229 216 208 200 Antibody Negative 568 550 538 526 506 487 480 470 460 449 Transiently Positive 20 19 18 16 16 16 15 14 14 14 Persistently Positive 37 32 26 25 24 22 22 19 16 15 *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo Calabresi et al, Neurol 2007
  • 18. 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
  • 19. Monitoring effect of therapeutic interventions
  • 20. Reduced efficacy due to NAbs – systematic review Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
  • 21. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis Sorensen et al. Lancet 2003; 362: 1184–91.
  • 22. Mean change in EDSS Malluci et al. Neurology 2004.
  • 23. Predictive markers for response to interferon therapy in patients with multiple sclerosis Malucchi et al. Neurology 2008;70:1119–1127.
  • 24. Jacob Elkins, James Sheridan, Lakshmi Amaravadi, Katherine Riester, Gilmore O’Neill Neurology 2012;78(Suppl.): S31.004
  • 25. Prognostic markers
  • 26. Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  • 27. Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  • 28. CSF NFLGunnarsson et al. Ann Neurol 2010; Epub.
  • 29. Can you help?www.ms-res.org
  • 30. www.ms-res.org
  • 31. N = 145
  • 32. CSF NFLGunnarsson et al. Ann Neurol 2010; Epub.
  • 33. Conclusion• Diagnostic/prognostic biomarkers • Intrathecal OCBs • Monoclonal IgM • IgG Index • Anti-lipid antibodies• Pharmacovigilance • Baseline screening • Monoclonal gammaopathy (IFNbeta) • Serology – VZV, JCV (immunosuppression) • TB screening (immunosuppression) • IL7:IL21, TPO (alemtuzumab) • 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
  • 34. Acknowledgements • Giovannoni • Charles ffrench-Constant • Sharmilee Gnanapavan • Robin Franklin • Siddharthan Chandran • David Baker • David Hampton • Gareth Pryce • Ian Duncan • Sarah Al-Izki • Sam Jackson • Sam Jackson • Peter Calabresi • Katie Lidster • Avi Nath • Yuti Chernajovsky • Raj Kapoor • Alex Annenkov • John Zajicek • Anne Rigby • Doug Brown • Michelle Sclanders • UK MS Clinical Trial Network • Larry Steinman • BioMS • Peggy Ho • Co-investigators • NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial

×