defining a disease

Defining a disease: the effect of incorporating biomarkers into clinical practice

Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine

December 2014

Disclosures

Over the last 15 years Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec for making available data slides on daclizumab for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.

Professor Giovannoni’s tour to Canada has been kindly sponsored by Biogen-Idec, therefore please interpret anything he says about Biogen-Idec’s products in this context.

This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.

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

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

What is multiple sclerosis?

.

Jean-Martin Charcot (1825-1893)

• Link between the hitherto mysterious symptomatology, now known to be MS, and the pathological changes seen in post-mortem samples.

• Charcot's triad – diplopia (double vision) – ataxia (disturbances of balance or

co-ordination) – dysarthria (difficulties with, or

slurred speech)

• Histological of MS lesions – loss of myelin – proliferation of glial fibres and

nuclei.

Multiple Sclerosis is a clinico-pathological correlate

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of axonal

loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e. involvement of

two or more white matter structures (space) separated by time,

with no other aetiology.

Diagnostic Tautology!

Conventional Definition:

Pathology

Pretheoretical definition:

Clinical

What is a disease?

What is a disease/what is MS?

A. Conventional definition

• E.g. “hepatitis is inflammation of the liver”

B. Pre-theoretical definition

• “SLE is characterised by the ARA criteria”

• Indirect definition

• Usually “polythetic”

• Inclusive definition using multiple characteristics

• According to Wittgenstein's model of a "long rope twisted together out of

many shorter fibres.“*

C. Theoretical definition

• E.g. “Down’s syndrome is trisomy 21”.

• Usually “monothetic”.

*Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).

Medical Philosophy

Ludwig Wittgenstein 1889-1951

Long rope twisted together out of many shorter fibres

Neurologists vs. Psychiatrists

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

Less active CIS

More active CIS

Less active RRMS

Active RRMS

Will Rogers Phenomenon in RRMS

Active RRMS

Less active CIS

CIS CDMS

MS CIS

Poser, et al. Ann Neurol 1983;13:227-31.

McDonald, et al. Ann Neurol 2001;50:121-7.

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

Not PPMS

Possible PPMS

OCB-ve

PPMS OCB-ve

PPMS OCB+ve

Will Rogers Phenomenon in PPMS

PPMS OCB+ve

Not PPMS

? PPMS PPMS

PPMS ? PPMS

McDonald, et al. Ann Neurol 2001;50:121-7.

Polman, et al. Ann Neurol 2005;58:840-6.

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. • Clinical diagnosis had been established by a neurologist in all cases. • Erroneous diagnosis included a variety of other neurological disorders.

Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.

518 CDMS (Schumacher & Poser)

418 (94%) MS

33 (6%) not-MS

Post-mortem

33 Probable MS (Poser)

22 (66%) MS

11 (33%) not-MS

Post-mortem

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 diagnosis

SPECIFICITY = 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.

Diagnosed MS

not diagnosed MS

Multiple Sclerosis

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

• Trauma

Miller DH. (1997)

Lennon et al. Lancet 2004;364:2106-12.

NMO

Diagnostic criteria for neuromyelitis optica (Devic’s syndrome)

Wingerchuk et al. Neurology 1999; 53: 1107–14.

Wingerchuk et al. Neurology 2006;66:1485-1489.

Phenotypic spread

Phenotypic spread

Pittock et al. Arch Neurol. 2006;63:390-396.

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

Accuracy of MRI for the diagnosis of MS: systematic review

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

Multiple Sclerosis is a clinico-pathological correlate

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of axonal

loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e. involvement of

two or more white matter structures (space) separated by time,

with no other aetiology.

20/170 (12%) patients (12 minimal non-specific & 8 zero MRI lesions)

Abnormal spinal MRI Spinal MRI

12 CDMS / LSDMS 1 clinically -probable MS

7 possible MS

Normal brain MRI

Differential diagnosis of suspected MS: a consensus approach

Miller et al. MSJ 2008; 14: 1157–1174

MS mimics

Neurosarcoidosis

• “Sarcoidosis is an inflammatroy multisystem

disorder of unknown cause.”

• “Neurosarcoidosis is a serious and commonly

devastating

complication of sarcoidosis.”

• “Solitary nervous system sarcoidosis is difficult

to diagnose.”

Hoitsma E, et al. Neurosarcoidosis: a clinical dilemma. Lancet Neurol. 2004 Jul;3(7):397-407. Review.

Zajicek et al. QJ Med 1999;92:103-117.

Zajicek et al. QJ Med 1999;92:103-117.

Diagnostic tautology

? disease

Describe the disease

Level 1: Descriptive study

Level 2: Diagnostic criteria

Developing polythetic diagnostic criteria

? Disease x

Disease X

Level 1: Diagnostic criteria

Disease Xy

Level 2: Diagnostic criteria

Level 4: Validate on different cohorts

Not Xy vs. Xy

Level 3: Comparison

Clinical, paraclinical, pathology, etc.

Neurosarcoidosis

Q: Was the diagnosis

neurosarcoidosis?

Study Eligibility Criterion (n = 531)

• A diagnosis of neurosarcoidosis in the differential diagnosis.

Inclusion Criterion A (n=85)

• A final diagnosis of neurosarcoidosis by a consultant neurologist.

Q: Was there histological

confirmation of non-

caseating granulomas?

Q: Was it a multisystem

disease?

Q: Was there no occupational or

surgical exposure to

inorganic foreign bodies?

Q: Was there no

alternative diagnoses?

yes yes yes

no

yes

Inclusion Criterion B (n=53)

• Histological evidence of sarcoid granulomas on an organ biopsy or Kveim test.

• Multisystem disease.

• No occupational or surgical exposure to inorganic foreign bodies.

• No alternative diagnoses

Inclusion Criterion C (n=25)

• Histological evidence of sarcoid granulomas on an organ biopsy.

Q: Was the histological confirmation of non-caseating granulomas based on

organ biopsy, i.e. sarcoid granulomas, vs. a Kveim test only?

Q: Was the onset of the neurological problems

more than 5 years since the tissue biopsy?

Q: Was there additional evidence of systemic sarcoid activity within 5 years of the

onset of the neurological problems?

no

yes

yes

yes

no

no

Inclusion Criterion D (n=22)

• If onset of neurological problems is more than 5 years after sarcoid granulomas were identified on organ biopsy, there must be additional evidence of systemic sarcoid activity within 5-years of the onset of the neurological problems.

Q: Was the histological

confirmation of sarcoid granulomas

obtained from neurological tissue?

Q: Was there histological or

additional evidence of sarcoid

granulomas outside the nervous system?

Inclusion Criterion E (n=4)

• Histological evidence of sarcoid granulomas within brain, spinal cord, meninges or nerves on biopsy. • Sarcoid granulomas outside brain, spinal cord, meninges and nerves are likely to be present on the basis of histological or other findings.

no

yes yes

no

Neurosarcoidosis

Diagnostic Category

No. patients

A

85

B

53

C

25

D

22

E 4

% intrathecal synthesis oligoclonal IgG

26% 13% 14% 5% 0%

Chamoun et al. To be resubmitted for publication.

New polythetic diagnostic criteria for neurosarcoidosis

Chamoun et al. Cambridge Thesis 1998.

Essential criteria to be fulfilled by all cases

a. Multisystem disease with neurological involvement compatible with sarcoidosis.

b. Neurological and systemic involvement must be temporally related with evidence of disease activity occurring within 5 years of each other.

c. No occupational or surgical exposure to inorganic foreign bodies.

d. No alternative diagnoses.

1. Possible neurosarcoidosis – clinically supported 1a - Clinically supported without Kveim testing

Clinical picture compatible with sarcoidosis.

1b – Clinically supported with Kveim testing

Clinical picture compatible with sarcoidosis and histological evidence of granulomatous reaction on Kveim testing.

2. Probable neurosarcoidosis - histologically supported by non-nervous tissue biopsy

Histological evidence of sarcoid granulomas on a non-nervous tissue biopsy.

3. Definite neurosarcoidosis - histologically supported by nervous tissue biopsy

Histological evidence of sarcoid granulomas on nervous tissue biopsy.

De Seze et al. Neurology 2001;57:1359-63.

• Tended to be female • Fewer brain MRI

abnormalities • Less likely to fulfill

criteria for definite PPMS

PPMS

n=10 (17%) SS / PPMS

n=60 PPMS

PPMS - SS

n=50 PPMS

n=10 (17%) SS / PPMS vs.

Conclusion: Sjögren’s myelopathy is not a disease yet; there is no clinicopathological correlate

Multiple Sclerosis PPMS

NMO OSMS

CIS TSP

? SS

ASYMP

AT RISK

NOT MS

MS

The evolving definition of MS

LHON

Important points

“What is a disease?”

“What is a disease?”

“What is a disease?” A patient’s perspective

A definitive diagnosis is important for several reasons: – Treatment

– Prognosis

– Knowledge

– Stigmatising

– Family counselling

– Disability Allowances

– Financial planning

– Insurance

– Etc.

Conclusion

• The diagnosis of MS relies on a pretheoretical definition – This doesn’t define MS as a biological disease

– Current diagnostic criteria are a moving target

– Not everybody who fulfils the current diagnostic criteria for MS has MS • Specificity ~95%.

– People almost certainly have MS who don’t fulfil the current diagnostic criteria • Sensitivity ?

– Current diagnostic criteria difficult to implement clinically

• We can’t diagnosis pre-symptomatic disease – Important for preventative and curative strategies

• We can’t identify people at-risk of MS – Important for preventative strategies

• There is a philosophy and a science behind defining a disease

• Inaccurate and accurate diagnosis have major implications

• Undiagnosing MS is hard