Update in body fluid markers giovannoni 25 jan 2013

Update in body fluid markers

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

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

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

0 1 2 3 Years

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rogr

essi

ng

Positive Negative

CSF

Slide courtesy of Jerry Wolinsky

P =0.03

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.

Pharmacovigilance markers

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.

312 cases -5th December 2012 69 (22%) died 243 (78%) alive

Mild disability – 10% Moderate disability – 50% Severe disability – 40%

5% NAbs – infusion reactions

Natalizumab PML risk stratification tool

Mitoxantrone

Azathioprine

Methotrexate

Cyclophosphamide

Mycophenolate

Cladribine

Rituximab

Etc.

Anti-JCV 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 14,285 1 in 1,666 1 in 192 1 in 94 1 in 555

Highest Lowest

Neurology 2012;78(Suppl.): [S41.006]

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-2

1

1.0

Se

nsit

ivit

y

0.8

0.6

0.4

0.2

0.0 0.0 0.2 0.4 0.6 0.8 1.0

1.0

Se

nsit

ivit

y

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

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

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*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

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo

0.73

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

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

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

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.

Mean change in EDSS

Malluci et al. Neurology 2004.

Predictive markers for response to interferon therapy in patients with multiple sclerosis

Malucchi et al. Neurology 2008;70:1119–1127.

Jacob Elkins, James Sheridan, Lakshmi Amaravadi, Katherine Riester, Gilmore O’Neill

Neurology 2012;78(Suppl.): S31.004

Prognostic markers

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

Can you help?

www.ms-res.org

ww

w.m

s-re

s.o

rg

N = 145

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

Conclusion • Diagnostic/prognostic biomarkers

• Intrathecal OCBs

• IgG Index

• 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

• Monoclonal IgM

• Anti-lipid antibodies

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