2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM Eastern
New Developments in ME/CFS Research
Alan R. Light, PhD
Research Professor of Anesthesiology
University of Utah
www.SolveCFS.org
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2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM Eastern
New Developments in ME/CFS Research
Alan R. Light, PhD
Research Professor of Anesthesiology
University of Utah
www.SolveCFS.org
“New developments in
research on ME/CFS”
Alan R. Light, Ph.D. Depts. Anesthesiology, and Neurobiology and
Anatomy: University of Utah School of Medicine
Ron Hughen (does everything)
Kathy Light (human research)
Andrea White (exercise scientist)
Cindy Bateman, M.D. (CFS clinician
extraordinaire)
Jie (Jesse) Zhang
Chris Benson, M.D.
Markus Amann
Supported by grants from:
Dept. of Anesthesiology
U of U School of Medicine
U of U
NINDS
NIHLB
SolveCFS
AFSA
Recent Advances in ME/CFS Research
• Three new publications indicate that
autoimmune disease may cause CFS in a
subgroup of patients.
• Two of these papers suggest that it might
be treatable in some of these patients
“New developments in research on ME/CFS”
•
#1. Autoimmune Basis for Postural Tachycardia Syndrome
•
Hongliang Li, Xichun Yu, Campbell Liles, Muneer Khan, Megan Vanderlinde-Wood, Allison
Galloway, Caitlin Zillner, Alexandria Benbrook, Sean Reim, Daniel Collier, Michael A. Hill,
SatishR. Raj, Luis E. Okamoto, Madeleine W. Cunningham, Christopher E. Aston and David C.
Kem
J Am Heart Assoc.2014; 3: e000755originally published February 26, 2014
• Postural Tachycardia Syndrome is common in a subset of patients
with ME/CFS
• It involves a rapid increase in heart rate when standing up
• Unlike other forms of orthostatic intolerance where blood pressure
remains low or decreases with standing, blood pressure can actually
increase with standing
• This investigation looked at 14 patients with POTS (postural
orthostatic tachycardia syndrome) and 10 healthy subjects.
• They initially did the study unblinded on 7 POTS patients and 8
controls. Then used blinded samples from Vanderbilt University to
look at 7 more POTS patients and 2 controls.
“New developments in research on ME/CFS”
• Autoimmune Basis for Postural Tachycardia Syndrome
• Briefly, this report indicates that in patients
with POTS, a condition that many CFS
patients have, most if not all of their
symptoms may be caused by auto antibodies
against components of the cardiovascular
system
“New developments in research on ME/CFS”
Beta adrenergic receptor gain of function autoantibodies are present in
POTS patients
Increase in beta 1 activity would cause the increased heart rate in these
patients, increase in beta 2 activity would decrease blood pressure
OKLA
VANDER
OKLA
VANDER
“New developments in research on ME/CFS”
Alpha Adrenergic receptor loss of function autoantibodies are present
in POTS patients
This would cause loss of normal vasoconstriction in POTS patients
OKLA
OKLA
VANDER
VANDER
“New developments in research on ME/CFS”
• #2. The Norwegian Group published the results of a new
trial in July 2015.
• B-Lymphocyte Depletion in Myalgic Encephalopathy/
Chronic Fatigue Syndrome. An Open-Label Phase II
Study with Rituximab Maintenance Treatment.
Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, et al. (2015)
PLoS ONE 10(7): e0129898.
• In 2009, this same group had done a case series that
indicated positive effects of Rituximab in some patients
with CFS
“New developments in research on ME/CFS”
• In 2011, this this group had done a small,
randomized, double-blind and placebocontrolled phase II study of 30 patients given
either rituximab (two infusions two weeks apart),
or placebo, with follow-up for 12 months.
• The primary endpoint was negative. There was
no difference between the rituximab and placebo
groups at 3 months follow-up.
• However, they had seen some evidence during
later followups that Fatigue scores improved
between 6–10 months after the treatment with
clinical responses in 2/3 of the patients receiving
rituximab
“New developments in research on ME/CFS”
• The new study is a follow up based on the longterm findings in their previous study
• The new study was an open-label, study with 29
patients.
• They were treated with rituximab - two infusions
two weeks apart, followed by maintenance
rituximab infusions after 3, 6, 10 and 15 months,
and with follow-up for 36 months.
• Results showed:
• lasting improvements in self-reported Fatigue
score, in 18 out of 29 patients
“New developments in research on ME/CFS”
• At end of follow-up (36 months), 11 out of 18 responding
patients were still in ongoing clinical remission.
• For major responders, the mean lag time from first
rituximab infusion until start of clinical response was 23
weeks (range 8–66).
• Conclusions: The observed patterns of delayed
responses and relapse after B-cell depletion and
regeneration, a three times higher disease prevalence in
women than in men, and a previously demonstrated
increase in B cell lymphoma risk for elderly ME/CFS
patients, suggest that ME/CFS may be a variant of an
autoimmune disease.
“New developments in research on ME/CFS”
• #3. Antibodies to ß adrenergic and
muscarinic cholinergic receptors in
patients with Chronic Fatigue Syndrome
• Madlen Loebel, Patricia Grabowski, Harald Heidecke,
Sandra Bauer, Leif G. Hanitsch,Kirsten Wittke, Christian
Meisel, Petra Reinke, Hans-Dieter Volk, Oystein Fluge,
OlavMella, Carmen Scheibenbogen. Brain, Behavior,
and Immunity (October 2015)
• This was a collaboration between a German group who
are experts in Elisa for autoantibodies and the previous
Norwegian group who did the Rituximab treatment trial
“New developments in research on ME/CFS”
• Approximately 30% of the 268 patients with CFS had
autoantibodies against beta 2 adrenergic receptors and
or acetylcholine receptors
• Responders to B cell reduction therapy from the previous
trial (Rituximab) included 15 out of 25 treated CFS
patients, while nonresponders were 10 of the 25.
• Many of the responders had high levels of
autoantibodies against beta adrenergic receptors or
acetylcholine receptors.
• The levels of these autoantibodies decreased to normal
levels following successful treatment with Rituximab.
“New developments in research on ME/CFS”
“New developments in research on ME/CFS”
• These reports, and our own published gene
expression studies in which 30% of patients with
ME/CFS showed a large decrease in adrenergic
alpha receptors following exercise and had
orthostatic intolerance convinced us to look for
auto antibodies in this specific group of CFS
patients.
• Currently, Dr. Madeline Cunningham and Dr.
Kem are running blinded autoantibody assays
on serum from CFS patients we provided to
them.
“New developments in research on ME/CFS”
• We recently conducted a double blind, cross over trial of pregabalin
(Lyrica) for Fibromyalgia and Chronic Fatigue Syndromes.
• We did this trial because our gene expression studies indicated that
pregabalin and gabapentin were effective in normalizing gene
expression and decreasing pain and fatigue in a subset of our
patents.
• Disclosure: This was an Investigator Initiated Grant from Pfizer
The results can and will be published freely, after allowing Pfizer a
prior look at the manuscript.
•
•
Treatment Protocol
We examined pre- and post-exercise leukocyte gene expression changes
induced by pregabalin in 10 patients with FM alone and 10 patients with
both CFS and FM.
•
In each of the 2 patient groups, 5 patients were randomly assigned to
receive pregabalin as Treatment 1, and 5 others received pregabalin as
Treatment 2.
•
Initial total daily doses were 150 mg, then titrated upward over 2 weeks to
achieve 300-450 mg, then maintained at the highest effective and tolerable
dose for 3 additional weeks.
Results
All Patients
N=20
FM only
N=9
CFS+FM
N=11
2 male, 18 female
1 male, 8 female
1 male, 10 female
Responders, N=13
6 CFS+FM, 7FM
Non-Responders, N=7
5 CFS+FM, 2 FM
1 male, 12 female
1 male, 6 female
In responders, large improvement in symptoms:
24 points for pain, 19 points for physical fatigue,
15 points for mental fatigue,
100
100
100
9090
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
20
10
10
10
0
00
Physical
Mental
Pain Fatigue
Fatigue
on Lyrica
on Lyrica
on Placebo
on Placebo
on Lyrica
Pain
MFbase
PFbase
base
Pain
MFmid
PFmid
mid
Pain
MFimm
PFimm
imm
on Placebo
Pain
MF30
PF30
30
min
Pain
MF8
PF8
8
hr
Pain
MF24
PF24
24
hr
Pain
MF48
PF48
48hr
Heart rate is decreased during exercise for most patients who respond to Lyrica
Even though these patients actually do more work during the exercise when on
Lyrica.
Heart rate for Lyrica Responders on Placebo vs on Lyrica
Placebo
Lyrica
Heart rate for Lyrica Non-Responders on Placebo vs on Lyrica
160
160
150
150
140
140
130
130
120
120
110
110
100
100
90
80
Placebo
Lyrica
90
80
Gene Expression Changes with
Lyrica
ASIC3
This graph compares the gene expression changes
caused by exercise in controls vs. patients
P2X4
1.5
Non-responding
patients
onon
Lyrica
Lyrica
Responding
Patients
placebo
Non-responding
Lyrica
Responding
Patients
Patients
on
on
Placebo
Lyrica
TRPV1
1.4
COMT
* *
1.3
TLR4
P2X7
1.2
TNFbeta
*
1.1
1
baseline
baseline
0.9
*
0.8
8 hr
0.7
24 hr
48 hr
8 hr
24 hr
48 hr
Conclusions
• Pregabalin can be at least a short term
treatment for a subset of CFS patients as
well as for a subset of FMS patients
• Some patients can have a worsening of
symptoms when given pregabalin
• Physiological measures are associated
with behavioral improvement in CFS
symptoms caused by pregabalin
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