Overview ofSjogren’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

• 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 Syndrome-is important to recognize and treat

but receives little attention even from the American College of Rheumatology

• “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

• “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 lidliterally sticks to

the surface epithelial surface and pulls

surface mucin layers off. The Rose Bengal

dye retentionis like

“rain water pooling in a street pothole”

This test can be done at bedside

and allows“triage” and rapid referral of patientsto 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 auto-antibodies. 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 salivationsecretion requires a functional unit

Nerves on mucosal4. Stimulation

of gland

2. Midbrain ofcentral nervous

system3. Stimulationof blood vessel

Afferent nerves

3. Cortical OutflowTractsand HPA

Lacrimatory or salivatory nuclei

watermucinprotein

waternutrientshormones

1. Ocular or oral surfaceirritation

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

Focal lymphocyticinfiltrates in the

glands

lymphocytes

Gland dysfunction•Autoantibodies (anti-muscarinic antibody)

Cytokines (type I IFN, -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

Sjogren’s Normal

Foci of lymphs

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

1. T- and B-cells have surface “homing receptors” when generated in node or marrow.

CD4+CD4+

B cellB cell

BloodBlood

3. When the homing receptor encountersvascular adhesive molecules,the lymphocyte enters tissue.

2. Lymphs migrate through blood

to tissues.

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.

GeneticFactors

(including sex)(HLA-DR)

GeneticFactors

(including sex)(HLA-DR)

GeneticFactors

(including sex)(HLA-DR)

GeneticFactors

(including sex)(HLA-DR)

Auto-antibodies

AcquiredImmune system

(HLA-DR)T/B-cells

DiseaseManifestations

Time period of years

InnateImmune system

(Toll receptor)

GeneticFactors

(including sex)(HLA-DR)

EnvironmentalFactor

(virus-such as EBV)(apoptotic fragment)

Type I IFNImmunecomplex

Ref. 32-33

Overview of Symptoms

When we get “flu symptoms” of joint pain, fatigue, foggy thinking—

it is a result of the lymphocyte hormonesreleased 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 -2Why 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

FatigueCognitive

Nervepain

Dry eyes and dry mouth

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.”

0

Neuroplasticity in Pain Processing1-3

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.

Stimulus Intensity

100

Pain state Normal

Allodynia

Hyperalgesia3

80

60

40

20

innocuous noxious

Pai

n S

ensa

tio

n

Cytokines alter pain perception

The Pain Roadmap: Peripheral and Central Nervous System Landmarks

Brain image courtesy of ATI

Peripheral Nervous System

Central Nervous System

• The neural processing of pain involves the:

– peripheral nervous system

– spinal cord (central nervous system)

– brain (central nervous system)

Brain Regions that May Modulate Pain and Emotion1-4

Prefrontal Cortex

Hippocampus

Insular Cortex

Thalamus

Somatosensory Cortex

Both

Pain

Central Amplification of Pain from Eyes and Mouth: Regions Found on Functional MRI

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

RobertFoxMD@mac.com

The Body’s 2 Distinct But Interconnected Immune Systems

ACQUIRED

Lymphyocytes (Type 2 interferon signature)

Beutler B et al. Blood Cells Mol Dis. 1998;24:216-230.

HLA-DR4–dependent:

T cells respond to peptide

antigens and generate

memory cells

INNATE

Dendritic Cells(Type 1 interferon signature)

HLA-DR–independent:

Dendritic cells respond to specific structures found on bacteria and apoptotic

Products (Toll receptors)