Transcript - Robert Fox, MD, Ph.D.

Sjogren’s Syndrome:
Pathogenesis and New Directions for Therapy
Robert I. Fox, M.D., Ph.D.
Carla M. Fox, R.N.
Scripps Memorial Hospital
Scripps Memorial/XiMED
La Jolla, California
[email protected]
Goals-1
Recognize that:
• Sjogren’s has benign symptoms (dry
eyes/mouth), fatigue, myalgias and
cognitive impairment.
• These symptoms are are the largest factor in
patient “disability”– although not well
treated by either local or biologic therapy.
Goals-2
• Systemic manifestations (rash, arthritis,
myositis, lymphoproliferative, biomarkers)
• These respond much better to systemic
therapy.
• Targets correspond to genes identified in
genomic screens.
• Characteristic cytokine, mRNA and gene
methylation/acetylation maps.
Goals-3
• The ability to improve extraglandular
manifestations but not “pain/cognitive”
indicates that we are missing an important
nociceptive pathway.
• New advances in neuroprotection in
Multiple Sclerosis provide new
opportunities to target microglial cells
Roadblocks to
Treatment of Dry Eyes and Dry Mouth
• Problems with study design
• Poor correlation with objective clinical and
laboratory values
• Concept of “functional circuit” not
recognized by immunologists or Pharma—
while it is the basis for neurologists and
pain therapy
Goals for Therapy
Fatigue, Myalgias and Cognitive Impairment
• This is the “holy grail” of neuro-immunology to solve in
the next decade.
• Flu-like symptoms, “ jet lag,” or after treatment of hepatitis
C with IFN.
• We have animal models from duloxetene (now for back
pain) or modafinil (jet lag)
• Molecular targets such as mTOR and AKT need to be
considered.
Fatigue and
Cognitive Impairment
• Much more common in SS or SLE
than in RA What is that telling us about pathogenesis?
• Involves the neuro-endocrine-immune axis
associated with “stress” response
(hypothalamic-adrenal axis)
which we must add
to innate and acquired responses as targets
Background-1
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-2
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
W
T
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
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
The Pain Threshold is Lowered in the Tsp (-/-) mouse
A pain stimuli that is innocuous in Wild Type
does cause nociceptive
pain inProcessing
tsp (-/-) mouse model1-3
Neuroplasticity
in Pain
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 AI, Jessell TM. The perception of pain. In: Kandel ER, et al, eds.
•Le Bars
D,ofAnimal
models
of Nociception. Pharmacological reviews 2001;53:597Principles
Neural Science.
4 ed. 2000:479.
th
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.
Similar pattern of
Fos-ir in PVH neurons
in response to distinct stressors
Emotional
Physiological
Neuroinflammation plays a prominent role
in the pathophysiology of several
neurodegenerative disorders, including
Multiple Sclerosis and Sjogren’s
syndrome.
Microglia contribute to initiating and
maintaining brain inflammation, and once
activated release pro-inflammatory
mediators potentially cytotoxic, like nitric
oxide (NO)
mTor and AKT pathway have multiple targets
for drug screening
in response to cytokines screening
mmt
mTOR inhibitors reduced NOS activity
and NOS2 expression induced by
cytokines, but not those induced by LPS.
In conclusion, mTOR selectively controls
microglial activation in response to proinflammatory cytokines and appears to
play a crucial role in microglial viability
Review of Sjogren’s Systemic
• From the point of view of rheumatologist
EYE DRYNESS results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s Syndrome
The upper lid
literally sticks to the
Epithelial surface
and pulls surface
mucin layers off.
The Rose Bengal
dye retention test
is like
“rain water pooling
in a street pothole”
This test can be
done at bedside
and allows
“triage” and rapid
referral of patients
to Ophthalmology
Severe “Xerostomia” (dry mouth)
with dry tongue
Angular
cheilitis
(candida)
Therapy of “benign” symptoms
a. dry eyes
b. painful eyes
c. dry mouth
d. painful mouth
e. fatigue
f. myalgias
Symptomatic and objective
findings are poorly correlated.
For this audience,
I will not review the myriad of
artificial tears and salivas.
I review these on my website
(in downloadable files for patients)
to facilitate providing information
to patients.
robertfoxmd.com
Simple Reminders:
a. artificial salivas or secretagogues
will not work until
you treat the oral candida first.
b. artificial tears with preservatives
cannot be used more than
4 times a day,
and will not work
until you treat blepharitis
Cortical Map for Corneal Pain
Figure 3
Hypothalamic Axis
• We also know from the high frequency of
autonomic dysfunction, that we have not yet
influenced the secondary effects on the
hypothalamic axis.
• We know that prednisone works, but we can
not therapeutically obtain the same benefit
in SS from other medications.
Extraglandular Manifestations
• May be Lupus-like (immune complex)pleurisy, hemolytic anemia, ITP, vasculitis
• May be lymphocytic infiltrateInterstitial pneumonitis, RTA, lymphoma,
neuropathy (central nervous or peripheral)
• Measured by ESSDAI scale (weighted by
importance)
Therapy
for
Extraglandular Manifestations
• Manifestations correlate with acute phase
reactants and biomarkers
• Manifestations respond to systemic therapy
such as rituximab, abatacept, belumimab,
anti-CD22 (epratazumab)
Sjogren’s Syndrome – with parotid enlargement
indicates lymphoproliferative tendency
Scleritis (vasculitis)
But in today’s
“super speed medicine”
• Not everything is so simple
• Caution that it is not a simple systemic
manifestation of SS
Ulcerative keratitis
(in patient given broad spectrum antibiotic
plus anesthetic)
Not all rashes are disease flares
Patient with NSIP who developed
pneumocystis on therapy
Steps in Pathogenesis
• Homing to specific tissues (glands)
• Production of autoantibodies
• Pathogenesis of salivary gland lesions
A key “target” in Sjogren’s
is that lymphocytes “home” to the glands
3. When the homing receptor encounters
vascular adhesive molecules,
the lymphocyte enters tissue.
CD4+
Blood
2. Lymphs
migrate
through blood
to tissues.
B cell
1.
Lymphocytes have surface “homing receptors”
when generated in node or marrow.
Interfere with homing
(obligate apoptosis if not bind “addressin”)
• Natalizumab (Tsabri)- cell adhesion a4-integrin
• Odulimomab (ICAM, CD54, LFA-1)adhesion and migration
• Fingolimod (Gilenya)sphingosine-1 receptor
• CD22 (Epratazumab)
In Sjogren’s Syndrome,
many acini and ducts are spared
Sjogren’s
Normal
Gene expression profiling of minor salivary glands clearly distinguishes
primary Sjögren's syndrome patients from healthy control subjects
Arthritis & Rheumatism
Volume 52, Issue 5, pages 1534-1544, 5 MAY 2005 DOI: 10.1002/art.21006
http://onlinelibrary.wiley.com/doi/10.1002/art.21006/full#fig1
Time course of autoimmune response*
1. Genetic factors predispose to Sjogren’s
2. Environmental factors such as a viral infection may lead to formation of
autoantibodies.
2. Antibodies precede disease.
3. However, presence of antibody does not necessarily mean disease.
Environmental
Factor
(virus-such as EBV)
(apoptotic fragment)
Innate
(Toll receptor)
Type I IFN
Genetic
Genetic
Genetic
Genetic
Factors
Factors
Factors
Factors
(including
(including
(includingsex)
sex)
sex)
(HLA-DR)
(HLA-DR)
(HLA-DR)
(HLA-DR)
Autoantibodies
Immune system
Immune
complex
Acquired
Immune system
(HLA-DR)
T/B-cells
Disease
Manifestations
Time period of years
Ref. 32-33
The main cytokine targets match those
identified in genome wide screens
HLA-DR (T-cell), CTLA and IFN-g
NF-K /IkB
Homing receptor (CXCR5)
Type I IFN –IRF5, STAT4, TLR3/7/9 and
pkR (cytoplasmic sensor)
• B-cell activation –BLK, BAFF, IL12, and
A20 (TNFAIP3)
•
•
•
•
Previously Studied in SS
•
•
•
•
•
Anti-CD20 –glandular and extraglandular
Anti-CD22-epratazumab
BAFF (Blys)-ACR 2012 abstracts*
Abatacept (CD40 L)-ACR 2012*
Allogeneic mesenchymal cells-ACR 2012
abstracts and article in Blood
•
www.rheumatology.org/wren/acrsearch.asp?zoom_query=acr%20abstracts%2
02012&st=nocache&actn=search&dt=12/24/2012%202:29:59%20P
Limited Success with antibodies to
type I IFN in SS
• In animal and early clinical trials, little
benefit after the disease is established—
although may help delay onset.
• Novel new target IRF8 and SLAC4A,
molecules that links TLR and IFN-type 1,
appear more promising
Other Inhibitors of IFN
a. Initial trials of anti-type 1 IFN
had infusion reactions and only
modest efficacy.
b. Medi 546 (type 1 IFN-R antagonists)
now in phase 1 (scleroderma)
and juvenile SLE phase 2 trial.
Now we have methylation maps
These methylation maps show different targets
Summary
Sjogren’s syndrome represents the interface of:
a) Immune and exocrine secretory functions (dryness)
b) Immune and neural function (neuropathy/cognitive)
c) Immune and hypothalamic-adrenal axis (endocrine)
d) Autoimmune proliferation and lymphoma
e) Lupus-like features of vasculitis and immune complex
Thank You
It is an honor to visit with you today
The slides are available on my website
RobertFoxMD.com