Classifying seronegative MG:A population based study

A Carr1,4, MI Leite2, A Vincent2, C Cardwell3, P McCarron3, D O’Reilly3, J McConville1,4

1. Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland.

2. Neurosciences Group, John Radcliffe Hospital, University of Oxford, UK

3. Department of Medical Statistics and Epidemiology, Queens University, Belfast, Northern Ireland.

4. Department of Neurology, Ulster Hospital Dundonald, Belfast, Northern Ireland

Aims

1. Describe the epidemiology of MG in Northern Ireland

2. Classify cases by serological subtype

3. Assess the usefulness of recently developed techniques

Methods

•Multiple sources of case ascertainment

•Study period: 01/01/2000 – 31/12/2008

•Clinical confirmation and serological classification of individual cases

•Characterisation by age, sex, symptomatology, diagnosis, treatment and co-morbidities

Results• 717 possible cases• 287 excluded • 342 prevalent cases (31/12/2008)• Ascertainment= 98.2% (95%C.I.: 92.1, 99.6)

• 212 incident during study period– 186 AChR MG– 26 SNMG

Serological analysis• 23 SNMG• 12 AChR MG• 6 MuSK MG• 4 Healthy controls (HC)

MuSK Ab (RIA)

AChR MG MuSK MG SNMG HC0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

EGFP

AChR+rapsyn-EGFP

Serum+ anti-human IgG

Serum+ anti-human IgG

MuSK-EGFPSerum+

anti-human IgG Merged

Cell-based immunofluorescent assay: MuSK

Case

Case

Control

AChR+rapsyn-EGFP

Serum+ anti-human IgG Merged

Cell-based immunofluorescent assay: clustered AChR

Case

Case

Control

Cell-based immunofluorescent assayCBA: AChR clustered with Rapysn

0

1

2

3

4

CB

A s

co

re

CBA: MuSK

0

1

2

3

4

CB

A s

co

re

Characteristics of serological subgroups

AChR MG MuSK MG Cluster ab MG SNMG PNP MG0

25

50

75

100

Ag

e at

on

set

(yea

rs)

AChR MG MuSK MG Cluster ab MG SNMG PNP MG0.00

0.25

0.50

0.75

1.00Male

Female

Pro

po

tio

n

AChR MG MuSK MG Cluster ab MG SNMG PNP MG0.00

0.25

0.50

0.75

1.00OcularGeneralised

Pro

po

rtio

n

AChR MG MuSK MG Cluster ab MG SNMG PNP MG0.00

0.25

0.50

0.75

1.00MGFA 1MGFA 2MGFA 3MGFA 4MGFA 5

Pro

po

rtio

n

No difference. ANOVA; p: 0.065 No difference. 2; p>0.5

No difference. ANOVA; p: 0.898 No difference. ANOVA; p: 0.393

Incidence rate (cases per million person-years)

CIR (x10-6) Number 95% C.I.

All MG 13.9 212 12.2 15.8

AChR MG 12.3 186 10.7 14.1

(Low affinity AChR ab 0.5 8 0.2 1.0)

MuSK MG 0.1 3 0.03 0.5

SNMG 0.8 12 0.5 1.4

PNP MG 0.9 0.5 0.5 1.6

Conclusions

• Cell based assays improve serological classification of autoimmune MG

• A proportion of cases remain seronegative

Acknowledgements

Prof Angela Vincent, Neurosciences group, Oxford University

Dr Isabel Leite, Neurosciences group, Oxford University

Neuromuscular junction

Muscle end plate

Motor neurone

•AChR ab in 80%•MuSK ab in 10%•SNMG 10%

Acetylcholine receptor

MuSK

Dok-7Rapsyn

Acetylcholine vesicle

Pre-synaptic Ca2+ channel