Transcript - Robert Fox, MD, Ph.D.

Overview of
Sjogren’s Syndrome:
Robert I. Fox, MD., Ph.D.
Scripps Memorial and Ximed
La Jolla, CA
It is a great honor to provide an overview for our
distinguished experts
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Dr. Stephen Cohen--Eye
Dr. Avu Wu--Mouth
Dr. Daniel Sauder--Skin
Dr. Fisher--Sleep
Dr. Nichols--GI
Dr. Wallace--Lupus
Dr. Cohen--New Drugs
Goals
• 1. Emphasize that evaluation of Sjogren’s is
different from a disorder like Rheumatoid Arthritis
• 2. Recognize that Sjogren’s patient has symptoms
that often do not correlate closely with laboratory
abnormalities
• 3. In development of future therapy, we have to
take a broader point of view to understand the
basis of Sjogren’s symptoms
Sjogren’s Syndromeis important to recognize and treat
but receives little attention even from the American College of Rheumatology
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“Quality of life”- patients equated the impact of dryness in Sjogren’s on their life
a) at same level of limitation as patients with moderate angina
b) they are willing to give up 2 years of life!!! to not have this condition
Factors not generally considered or measured
with lab tests
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“Disability” is most commonly due to fatigue and cognitive impairment
“Limitations” on daily activities:
 dry eyes (limits work- especially computer)
 dry mouth (limits sleep and social interactions around eating)
 extra-glandular manifestations, particularly neurologic
• “Expense of artificial tears and dental decay
Typical Clinical Features of
dry eyes, dry mouth
and swollen glands
Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s syndrome
The upper lid
literally sticks to
the surface epithelial
surface and pulls
surface mucin layers off.
The Rose Bengal
dye retention
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 with dry tongue
Sjogren’s Syndrome- Cervical Dental Caries
In Sjogren’s syndrome:
there is often a poor correlation
between how the patient feels and
the laboratory tests.
This frustrates both patients and
doctors.
The labs and the symptoms:
Take Home Lessons-1
We measure blood counts, sedimentation rates and autoantibodies. This gives an idea of the “activity” of the
immune system based on lymphocyte hormones.
However, these lab tests do not often correlate well with
the patient’s symptoms.
The key to understanding this
imbalance of labs and symptoms
Recognition that lymphocyte hormones
(which is what we are really measuring
indirectly through our lab tests) influence:
• the nerve’s function to activate glandular
secretion
• the nerve’s ability to transmit sensations of
pain or discomfort
The Functional Circuit
• The functional circuit refers to the
“nerve” input from eye and mouth to the
central nervous system.
• In other words, the threshold for sensing
“pain or dryness” may differ in individual
patients.
Normal tearing or salivation
secretion requires a functional unit
4. Stimulation
of gland
water
nutrients
hormones
3. Stimulation
of blood vessel
water
mucin
protein
3. Cortical
Outflow
Tracts
and
HPA
1. Ocular or oral surface
irritation
Nerves on mucosal
Afferent nerves
2. Midbrain of
central nervous
system
Lacrimatory or salivatory
nuclei
In Sjogren’s syndrome, the release of neural transmitters
--and the response of the glands to neural transmitters-are impaired by lymphocytes
that enter the gland and release inflammatory factors
ocular and oral dryness
lymphocytes
Focal lymphocytic
infiltrates in the
glands
Gland dysfunction
•Autoantibodies
(anti-muscarinic antibody)
Cytokines (type I IFN, g-IFN)
•Metalloproteinases
(outside-inside signaling
molecules)
In Sjogren’s, only 50% of the acini and ducts are destroyed.
Despite their retention of neural innervation, the residual
glands do not function as a result of the inflammatory
environment
Foci of
lymphs
Sjogren’s
Normal
Thus, the interesting question is:
Why are the residual glandular elements
not working?
This fundamental question of
how immune and neural systems interact
will be the “holy grail” of neuroscience
for the next decade.
In addition to the symptoms
SS has
lymphoproliferative properties—
it lies on the border between
autoimmunity and
lymphoma.
Sjogren’s Syndrome – with parotid enlargement
indicates lymphoproliferative tendency
The normal salivary gland is not a lymph node.
Why are there lymphocytes in the salivary gland?
Part of the cause of 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.
T- and B-cells have surface “homing
receptors” when generated in node or
marrow.
Time course of autoimmune response*
1. Genetic factors predispose to Sjogren’s
2. Environmental factor such as a viral infection leads to autoantibody.
2. Antibodies precede disease.
3. Presence of antibody does not 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
Overview of
Symptoms
When we get “flu symptoms”
of joint pain, fatigue, foggy thinking—
it is a result of the lymphocyte hormones
released by the immune system.
When these reactions persist in genetically
predisposed individual by the immune system,
the result is autoimmune disease.
Summary-1
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
Summary-2
1. Extraglandular manifestations are
determined by lymphocyte homing to
tissues-- factors that govern their
retention in tissues and their apoptosis.
2. Factors governing their clonal expansion
and lympho-proliferation lead to
lymphoma-derived from B-cells
themselves, T-cells, and dendritic cells.
Summary -2
Why is SS predominantly in women
• X-chromosome location of Toll receptor;
• X-linked genes for apoptosis;
• X-linked genes for transcription promoter of
pro-inflammatory loci including NF-K;
• X-linked control of metalloproteinase
release under hormonal regulation.
Treatment of Sjogren’s in 2012:
Opportunities and Challenges
a) Treatment of Dry Eyes and Mouth
b) Treatment of Extraglandular
Manifestations-• Lupus like symptoms-arthralgia, rash
• Neuropathy (central and peripheral)
• Cognitive and myalgia (fibromyalgia)
• Lymphoproliferative
Thank you for coming
• I will now take questions
• Or if there is time, I can describe a bit about
how we are approaching this problem of
functional circuit in association with
colleagues at Scripps and Salk
Neuropathy
• Poor correlation between symptoms and
objective findings:
– Eye pain- does not correlate with tear flow;
– Mouth pain-not correlate with saliva;
– Peripheral neuropathy-not correlate with nerve
biopsy;
– Cognitive-not correlate with acute phase
reactants.
Fibromyalgia:
The elephant in the Room
Fatigue
Cognitive
Dry eyes and
dry mouth
Nerve
pain
As rheumatologists
• We will need to learn a new vocabulary
about the perception of pain and how it is
modulated by cytokines.
• The key term is the “plasticity” of the
nervous system. How the perception of
pain is modulated by cytokines of the
“stress axis.”
Neuroplasticity in Pain Processing1-3
100
Pain Sensation
80
Hyperalgesia3
Cytokines
alter pain
perception
60
40
Pain state
Allodynia
20
0
innocuous
noxious
Stimulus Intensity
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.
Principles of Neural Science. 4th ed. 2000:479.
3. Cervero F, Laird JMA. Pain. 1996;68:13-23.
Normal
The Pain Roadmap: Peripheral and
Central Nervous System Landmarks
• The neural
processing of pain
involves the:
– peripheral
nervous system
– spinal cord
(central nervous
system)
– brain (central
nervous system)
Central
Nervous
System
Brain image courtesy of ATI
Peripheral Nervous
System
Brain Regions that May Modulate Pain and
1-4 and Mouth:
Central Amplification ofEmotion
Pain from Eyes
Regions Found on Functional MRI
Both
Somatosensory Cortex
Pain
Insular Cortex
Prefrontal Cortex
Thalamus
Hippocampus
Thank you
for your time and attention
I would be happy to entertain any questions
now or later.
The slides are available to you
for your use
at
[email protected]
The Body’s 2 Distinct But Interconnected
Immune Systems
ACQUIRED
INNATE
HLA-DR4–dependent:
HLA-DR–independent:
T cells respond to peptide
antigens and generate
Dendritic cells respond to
specific structures found
on bacteria and apoptotic
memory cells
Products (Toll receptors)
Lymphyocytes
Dendritic Cells
(Type 2 interferon signature)
(Type 1 interferon signature)
Beutler B et al. Blood Cells Mol Dis. 1998;24:216-230.