Transcript - Robert Fox, MD, Ph.D.

New Directions in Therapy for
Sjogren’s Syndrome
Robert I. Fox, MD., Ph.D.
Scripps-Ximed
La Jolla, CA
[email protected]
(all slides on my website www.robertfoxmd.com)
Goals
• Recognize that Sjogren’s has “benign” and
“systemic” manifestations
• Review the concept of “functional circuit” that
links the inflammation of the mucosal circuit
to the brain cortical regions that “sense pain”
• Discuss the potential target of microglial cells
and their cytokines/neurokines that may
influence the perception of pain/dryness in SS
Background-1
SS patients have Benign and Systemic Symptoms
• Systemic symptoms—rash, arthritis, lung, kidney,
lymphoma, hematologic--measured by ESSDAI which
measures 12 organ domains.
• Although ESSDAI usually less than 10, it has scale 0100.
• Improvement by at least 3.5 units is significant
• Benign symptoms—dry and painful eyes/mouth,
fatigue, cognitive, myalgia—measured by ESSPRI
Background-2
• Benign symptoms are leading cause of
disability as identified by SS patients and
poorly correlate with acute phase markers of
inflammation
• The failure to improve benign symptoms is the
main reason why current therapies have failed
in FDA trials
Background-1
Benign symptoms include:
• Dry and Painful eyes
• Dry and Painful Mouth
• Fatigue, and Myalgia
Background-2
Benign Symptoms
• These do not correlate well with acute phase
reactants
• They are more similar to “neuropathic” symptoms
and involve “nociceptive” pain circuits
• Nociceptive pain is caused when special nerve
endings—called nociceptors –are activated and
follow a particular pathway to cortex of brain
Use of Biologics in Systemic Manifestations of SS
We have had modest success with biologics as
measured by ESSDAI (clinical significance >3 units
improvement) in SS patients with early disease
•
•
•
•
Rituximab
Belimumab
Abatacept
Tocilizumab
Background-2
The functional Circuit
• To understand “benign symptoms” and
develop better therapies—we must review the
concept of the functional circuit in SS
• the interaction of immune activation on
microglial cells and associated neurons
• New targets include mTor and AKT pathways
Background-3
The functional circuit in SS
1. Mucosal Surface
(inflammatory cytokines
and metalloproteinase)
4. Gland
(lymphs, cytokines,
metalloproteinase)
2. Midbrain
Vth Nucleus
(lymphocytes
and glial cells)
3. Vascular
(iNOS, CAMs,
Chemokines)
These sites and their cytokines correlate
with systemic manifestations
Brain
Cortex
Nociception (pain)
glial cells and
corticcal neurons
We must understand
these sites to treat
“benign” symptoms
Does this apply to Sjogren’s syndrome?
• Patients with early SS had corneal pain that
decreased completely with topical anesthesia*
• Patients with chronic SS showed only a partial
(30% decrease) in eye pain after topical
anesthetic*
• Functional MRI (fMRI) showed nocioceptive
pattern—called phantom pain amplification
*Rosenthal et al
To study the mechanism of neurogenic or
nociceptive pain we must use animal model-1
• The thrombospondin (-/-) mouse (TSP null) or the TGF-b receptor
mutation both develop SS like disease
• The mouse develops both oral and ocular lesions
• The mouse develops ANA and SS-A antibodies
• Thrombospondin is a matrix protein that plays a role in activation of latent
TGF-b
• Activated TGF-b promotes Treg and inhibits Th-17 (IFN-g)
• Thus, TSP (null) has high levels of Th-17, IL-17 and IFN-g
Thrombospondin (-/-) mouse model of SS
4 wks
WT
24 wks
Lacrimal gland biopsies
Tsp-/-
The mouse has ANA+, SS-A+
TSP null can not activate TGF-b
In absence TGF-b , continuous Th- 17
TGF-b and cytokine activation stimulates mTor/AKT
The Pain Threshold is Lowered in the Tsp (-/-) mouse
A pain stimuli that is innocuous in Wild Type
does cause nociceptive pain in tsp (-/-) mouse model 1-3
Neuroplasticity
in Pain Processing
100
Pain Sensation
80
Hyperalgesia3
Thrombospondin (-/-)
Mouse at 24 wks
Where a trivial stimuli
Causes pain response
60
40
Pain state
Normal
Allodynia
Wild type
20
0
innocuous
noxious
Stimulus Intensity
•Ocular chemical stress model of nociceptive pain
1. Woolf CJ, Salter MW. Science. 2000;288:1765-1768.
2. Basbaum
Jessell TM.models
The perception
pain. In: Kandel ER, et Pharmacological
al, eds.
•Le Bars
D, AI,Animal
ofof nociception.
reviews 2001;53:597-652.
Principles of Neural Science. 4 ed. 2000:479.
th
At the level of the Vth nerve
(Tsp -/- mouse)
• Microglial cells translate inflammatory signals that go
to nociceptive cortex
WT
TSP (-/-)
mTor and AKT activated in
response to “lower stimuli”
in the tsp (-/-) mouse
Of interest, the same regions are activated with physiologic or
emotional stressors
Emotional
Physiological
Similar pattern of Fos-ir in cortical neurons in response to distinct stressors
Summary-1
• Functional circuit needs to be considered
when assessing “benign” symptoms of corneal
or oral pain
• Symptoms of oral/ocular pain do not correlate
with markers of systemic inflammation
(ESR/CRP) because the events are contained
within the brainstem and cortex
Summary-2
• Afferents go to midbrain regions of Cranial Vth
• Microglial cells are site of cytokine/neurokine
interaction
• Receptors and neurokines from microglial cells
are therapeutic targets
Summary-3
• Novel targets include mTor and AKT pathways
• These mTor/AKT pathways also implicated in
chronic pain and depression—so we must
collaborate with these neurochemists
Summary-4
• Cortical “memory” of nociceptive pain is well
described in neurologic literature
• fMRI indicates that nociceptive pain is the
cause of benign symptoms in SS that do not
correlate with acute phase reactants
Moulton et*. Al used fMRI in SS patients with chronic ocular pain
using fMRI of nociceptive pain have been studied
Cortical regions that
activate with ocular pain
signal at “benign stimuli
levels” occur only in
chronic SS patients with
severe pain
*Moulton EA, Becerra L, Rosenthal P, Borsook D. An Approach to
Localizing Corneal Pain Representation in Human Primary Somatosensory
Cortex. PloS one 2012;7:e44643.
Summary-5
• We have made advances in “systemic
inflammation” and these are encouraging
• For “drug licensing” we will also need to
improve the patient’s “quality of life”
symptoms of dryness, pain and fatigue
• We need for “autoimmune” divisions to work
with “neuro-chemistry” research divisions
どうもありがとうございました
Takayuki Sumida,MD.-President
Ichiro Saito, DDS (Tokyo)
Kaz Tsubota, MD (Tokyo)
Bruce Beutler, Ph.D. (Scripps TSRI)
Ari Theofilopoulos (Scripps TSRI)
V. Ramachandran, MD (Salk Neurology)
P. Rosenthal (Harvard Corneal Pain Unit)
We are also looking at
Additional Targets of Interests
Chemokines and their receptors (CCR) on vascular cells and lymphocytes
TLR receptors: SLAC-15 that links Toll receptor and type 1 IFN
Methylation modulators and siRNA
Neural mediator circuits:
• Receptors on cornea--substance P (TRPV1), VIP and CGRP pain receptors
• TRPM8, TRPA1, and CGRP in trigeminal ganglion neurons
• Trigeminal ganglion neurons- MCP-1, MIP-2,
• CCR and CCL at the blood brain barrier
CCR and Blood Brain Barrier
Similar pattern of
Fos-ir in PVH neurons
in response to distinct stressors
Emotional
Physiological
We need to examine microglial pathways
• Upon activation, microglia (M1 and M2)
secrete inflammatory mediators that
contribute to the resolution or to further
enhancement of damage in the central
nervous system (CNS).
• Particularly, the role of the
phosphatidylinositol 3-kinase
(PI3K)/Akt/mammalian target of rapamycin
(mTOR) and glycogen synthase kinase-3
The tsp-null mouse allows us to look at the interaction
of peripheral inflammation and microglial cells
• Activation of microglial cells through
mTor/AKT
• In absence of thrombospondin, constitutive
activation of Th17 and IFN-g activates
microglial cells
• Nociceptive (pain) pathway occurs through
smad3 and non-smad pathways that involve
mTor/AKT pathways in cranial nerve V