New Developments in ME/CFS Research 2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM...

New Developments in ME/CFS Research

2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM Eastern

Alan R. Light, PhDResearch Professor of Anesthesiology

University of Utah

www.SolveCFS.org

About Our Webinars• Welcome to the 2015 webinar series!

• The audience is muted; use the question box to send us questions

• Webinars are recorded, and the recording is made available on our YouTube channel

• SMCI is a research organization and does not provide medical advice

New Developments in ME/CFS Research

2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM Eastern

Alan R. Light, PhDResearch 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) ZhangChris Benson, M.D.Markus Amann

Supported by grants from:Dept. of AnesthesiologyU of U School of MedicineU of UNINDSNIHLBSolveCFSAFSA

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


• #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.


• 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 VANDEROKLA VANDEROKLA VANDEROKLA VANDEROKLA VANDER OKLA VANDER


OKLA VANDER

Alpha Adrenergic receptor loss of function autoantibodies are present in POTS patients

This would cause loss of normal vasoconstriction in POTS patients

OKLA VANDEROKLA VANDER

• #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


• In 2011, this this group had done a small, randomized, double-blind and placebo-controlled 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


• The new study is a follow up based on the long-term 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


• 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.


• #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


• 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.


• 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.


• 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

1 male, 10 female1 male, 8 female2 male, 18 female

CFS+FMN=11

FM onlyN=9

All PatientsN=20

1 male, 6 female1 male, 12 female

Non-Responders, N=75 CFS+FM, 2 FM

Responders, N=136 CFS+FM, 7FM

In responders, large improvement in symptoms:

24 points for pain, 19 points for physical fatigue,

15 points for mental fatigue,

Pain

Painbase

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Pain30 min

Pain8 hr

Pain24 hr

Pain48hr

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Physical Fatigue

PFbase PFmid PFimm PF30 PF8 PF24 PF48

on Lyrica on Placebo

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Mental Fatigue

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Heart rate for Lyrica Responders on Placebo vs on Lyrica

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Heart rate for Lyrica Non-Responders on Placebo vs on Lyrica

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Placebo Lyrica

Heart rate is decreased during exercise for most patients who respond to LyricaEven though these patients actually do more work during the exercise when on Lyrica.

Gene Expression Changes with Lyrica

This graph compares the gene expression changes caused by exercise in controls vs. patients

0.7

0.8

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baseline

8 hr 24 hr 48 hr

baseline

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ASIC3

P2X4

TRPV1

COMT

TLR4

P2X7

TNFbeta

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Lyrica Responding Patients on placeboLyrica Responding Patients on LyricaNon-responding Patients on Placebo

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Non-responding patients on Lyrica

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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Make ME/CFS understood, diagnosable and treatable.

Our StrategyStimulate participatory research aimed at the early detection,

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New Developments in ME/CFS Research 2015 Webinar Series | Thursday, October 15, 2015 | 1:00 PM...

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