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Dr Robert Cooper & Dr Hector Chinoy
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Meeting Report based on a talk given by Dr Chinoy printed in Newsletter 61, November 2006
Mini Conference: Adult Onset Myositis Immunogenetic Collaboration (AOMIC) Update
The work of the AOMIC is focussed on DM
(Dermatomyositis) and PM (Polymyositis). This is because, as rheumatologist,
Drs Cooper and Chinoy see DM and PM patients rather than IBM (Inclusion
Body Myositis) which is seen by neurologists. Why is this? Simply
because of the way the diseases initially present themselves. The
signs and symptoms of DM/PM typically lead to a referral to a rheumatologist
whilst those of IBM will lead to a neurologist. Therefore, in general,
a rheumatologist will manage DM/PM and a neurologist will manage
IBM patients.
 Dr
Chinoy presented his research findings for DM and PM, however, the
technologies can hopefully be one day assigned to JDM (Juvenile
Dermatomyositis) and IBM research. DM and PM are often clumped together
but these diseases themselves are distinct. For example, pathological
differences are seen in the muscle between DM and PM, a heliotrope
rash and an increased risk of malignancy is associated with DM,
and different serological associations have been noted for DM and
PM; for example auto-antibodies more common in DM are those against
Mi-2 and for PM anti-SRP antibodies are more common (figure 1).
The question being asked by Dr Chinoy and his colleagues is; "How
does PM and DM differ genetically?" And the reason they asked this
question is that they believe that by understanding the genetics
of a patient's myositis they will be able to understand and predict
the course of the disease and eventually be able to target the use
of certain therapies in the future. For example, with this knowledge
in the future, we will hopefully be able to say, if you have genotype
A you are likely to develop lung disease, or, if you have genotype
B you are more likely to respond to steroids than genotype C who
would benefit from an early use of methotrexate. Having the knowledge
to predict from a patient's genes their disease outcome would be
invaluable to the clinician in helping him manage and treat his
patient and would benefit the patient's quality of life.
 Dr
Chinoy gave an overview of genetics and the techniques they have
available to perform such studies. He described the genes of most
interest were a cluster of genes known to code for HLA proteins.
HLAs are involved in the immune system and certain HLA genotypes
have been associated with the development of autoimmune disease.
It has been suggested by Dr Fred Miller that myositis should be
re-classified according to serological profile as certain features
are closely associated with a specific serology. For example, rather
than DM or PM, the Myositis should be anti-synthetase myositis,
anti-SRP myositis or anti-Mi-2 myositis, etc., (figure 2). Dr Chinoy's
genetic data supports this idea. He found that certain genotypes
were more closely associated to serology than Myositis subtype (PM
or DM). For example, HLA-DRB1*03 was associated more with PM than
DM, however patients with anti-synthetase antibodies were more associated
with this genotype. Also, HLA-DRB1*07 was associated more with DM
than PM, however there was a greater association between this genotype
and Mi-2 auto antibodies.
The next stage of their work is to analyse their genetic findings
with patient histories. With this information they hope to be able
to draw conclusions regarding the disease course of a patient with
specific HLA genotypes.
This work had been published as a scientific paper; In adult onset
Myositis, the presence of interstitial lung disease and Myositis
specific/associated antibodies are governed by HLA class II haplotype,
rather than by Myositis Subtype.
Dr Cooper writing in Newsletter 59, October 2005
"It is a year since we last reported
the progress that we have made in respect of muscle genetics. The
early financial support provided by the Myositis Support Group enabled
us to do preliminary genetic testing, and on the back of this we
were able to submit a successful bid for an ARC Clinical Research
Fellow, in Dr Hector Chinoy. Hector has been in post for some eight
months now, and he has gathered considerable momentum in respect
of the genetic analyses. Over and above the initial laboratory based
genetics, the Myositis Support Group funding also enabled us to
send blood to Professor Chester Oddis's lab in Pittsburg, USA and
they have now analysed our myositis patients blood for myositis
specific antibodies (MSAs) and myositis associated antibodies (MAAs).
Chester's lab is one of probably only 3 or 4 in the world capable
of doing this testing. The results are very important, because they
help to further our understanding of disease mechanisms.
It is now 4 years since we started the Adult Myositis Onset Immuno-genetic
Collaboration (AOMIC), and we now have more than 380 bloods in the
Medical School in Manchester. Our initial hypothesis in undertaking
genetics was that DM and PM would genetically be different diseases
(in respect of the DM rash, the severity of muscle disease, MSA/MAAs
association likelihood of lung fibrosis etc). Our initial genetic
results demonstrated obvious differences in HLA Class II gene associations,
thus in support of our original hypothesis.
However, having now got the results of the MSA/MAAs from Professor
Oddis, it turns out that the situation is much more complex than
expected. As we have extended our genetic investigations of the
HLA Class II region, one of the most important genes in the body
for governing an individual's immune response, we have been able
to establish patients haplotypes. A haplotype is a set of closely
linked genes inherited as a unit and which tend to be very stable
against changes during species mating.
Thus if a haplotype did cause a disease manifestation, it would
be one that tended to be maintained throughout a population. We
have examined 6 or 8 of the most common HLA Class II haplotypes
known to be encountered in a normal European caucasian population.
Thus the haplotype HLDRB1*03 DQA1*05 and DQB1*02 is clearly a predisposer
for both PM and DM, however it also predisposes to the presence
of anti-Jo-1 antibodies in the blood. The haplotype was also highly
associated with lung fibrosis, even if anti-Jo-1 antibody is negative.
This haplotype was present in 48 out of 50 DM/PM patients with lung
fibrosis. This has got potentially very important messages for the
future, because if we knew at outset which individuals are predisposed
to get lung fibrosis, we would keep a much closer eye on them, and
we would probably also avoid the use of Methotrexate in such patients.
Thus a basic science approach may have already picked up a very
important clinical message.
Another haplotype is HLADRB1*07, DQA1*02 and DQB1*02, which is very
highly associated with the anti-Mi-2 antibody, also detected by
Prof Oddis. In fact, all the anti-Mi-2 antibody positive patients
had this haplotype. We are not yet sure what this antibody means
in terms of clinical disease expression, but of the 19 patients
detected with anti-Mi-2, 18 had DM, and none have lung fibrosis.
We are now checking haplotype types with other inflammatory genetic
markers. This is exciting and interesting and suggests that haplotype
not only governs myositis sub-type, but also clinical features such
as lung fibrosis, etc. The first big paper is in final preparation
for Arthritis and Rheumatism, and no doubt Fred Miller will be reviewing
this.
Lastly, Lucy Wedderburn and Co (Institute for Child Health at Great
Ormond Street) have now sent us more than 100 juvenile DM bloods,
so we will very soon be able to compare the genetic profile of adults
and children with DM. Adult patients with DM tend not to get overlap
features, whereas children often do, and indeed some children differentiate
to connective tissue disease other than myositis over time. It is
thus our suspicion that adults and juvenile DM will have different
genetic profiles."
Dr Cooper writing in Newsletter 57, November 2004.
"The Adult Onset Myositis Immunogenetic Collaboration
(AOMIC), which has now expanded to include 56 UK consultants, has
been running for 4 years, and collected more than 100 polymyositis
(PM) and more than 100 dermatomyositis (DM) patients' clinical details
and bloods for genetic analysis.
The preliminary genetic results confirm those of Fred Miller, but
because our myositis patient sub-groups are so homogeneous (i.e.
all Caucasian) and our sample sizes so considerably larger than
Fred's, we have been able to show clear genetic differences between
PM and DM. This is very encouraging, as it suggests that the statistical
power resulting from our larger sample sizes will enable us to detect
further genetic differences, and so to gain further insights into
the disease mechanisms underlying these myositis subtypes. Gaining
mechanistic insight is very important if therapeutic developments
are to follow.
As a result of the abstract-publishing of these preliminary results,
which have now been presented at both British and American Rheumatology
meetings, a successful bid was lodged with the ARC, which has now
funded Dr Hector Chinoy as a Clinical Research Fellow for 3 years.
Hector will work very closely with myself and Prof Bill Ollier to
further this important work.
Hector's job is to visit the centres contributing patients to AOMIC,
and to see and examine all of the recruited patients. This will
allow us to examine the effects of genetics on disease severity,
hopefully to be able to determine which patients have the more aggressive
disease, and thus to determine who needs the more aggressive treatment.
A more recent development is the possibility of a genetic collaboration
with the Juvenile DM group in Great Ormond St and the Institute
for Child Health (ICH). I recently met Prof Woo and Drs Lucy Wedderburn
and Clarissa Pilkington and there JDM research group recently in
ICH, and there was general agreement that collaboration is the way
forward, so long as certain problems can be ironed out. The JDM
group have around 100 JDM patients through a national collaboration
similar to AOMIC, so a genetic comparison of JDM and adult DM does
now look viable.
These are very exciting developments, and I would like to formally
thank the Myositis Support Group, who have and continue to financially
support our work in Manchester. I think the 3 year ARC fellowship
is a direct result of the results generated through the work, and
as this was in part funded through the Group, this contribution
needs recognition. The Group deserves congratulation on its contribution
to the academic progress made in such a short time. It was a great
pleasure to meet so many Group members at the Group's Manchester
meeting in Stockport, and many of you will meet Hector again in
the coming 12-18 months, as part of his ARC Fellowship work."
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