Overview of Sjogren

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Overview ofSjogrens Syndrome

• Robert I. Fox, MD., Ph.D.
• Scripps Memorial and Ximed
• La Jolla, CA

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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

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Goals

• 1. Emphasize that evaluation of Sjogrens is
  different from a disorder like Rheumatoid
  Arthritis
• 2. Recognize that Sjogrens 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 Sjogrens symptoms

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Sjogrens Syndrome-is important to recognize and
treatbut receives little attention even from the
American College of Rheumatology

• Quality of life- patients equated the impact of
  dryness in Sjogrens 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

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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

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Typical Clinical Features of dry eyes, dry
mouth and swollen glands
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Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)characteristic
of Sjogrens 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
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Severe Xerostomia with dry tongue
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Sjogrens Syndrome- Cervical Dental Caries
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In Sjogrens syndromethere is often a poor
correlation between how the patient feels and the
laboratory tests.This frustrates both patients
and doctors.
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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 patients symptoms.

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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 nerves function to activate glandular
  secretion
• the nerves ability to transmit sensations of
  pain or discomfort

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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.

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Normal tearing or salivation secretion requires a
functional unit
water mucin protein

• Ocular or oral surface
• irritation

4. Stimulation of gland
Nerves on mucosal
3. Cortical Outflow Tracts and HPA
water nutrients hormones
Afferent nerves
2. Midbrain of central nervous system
Lacrimatory or salivatory nuclei
3. Stimulation of blood vessel
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In Sjogrens 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

• Gland dysfunction
• Autoantibodies
• (anti-muscarinic antibody)
• ?Cytokines (type I IFN, g-IFN)
• Metalloproteinases
• (outside-inside signaling molecules)

lymphocytes
Focal lymphocytic infiltrates in the glands
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In Sjogrens, 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
Normal
Sjogrens
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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.
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In addition to the symptomsSS has
lymphoproliferative propertiesit lies on the
border between autoimmunity andlymphoma.
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Sjogrens Syndrome with parotid enlargement
indicates lymphoproliferative tendency
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The normal salivary gland is not a lymph
node. Why are there lymphocytes in the salivary
gland?
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Part of the cause of Sjogrens 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.

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Time course of autoimmune response 1.
Genetic factors predispose to Sjogrens 2.
Environmental factor such as a viral infection
leads to autoantibody. 2. Antibodies precede
disease. 3. Presence of antibody does not mean
disease.
Auto- antibodies
Innate Immune system (Toll receptor)
Environmental Factor (virus-such as
EBV) (apoptotic fragment)
Immune complex
Type I IFN
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Genetic Factors (including sex) (HLA-DR)
Disease Manifestations
Genetic Factors (including sex) (HLA-DR)
Acquired Immune system (HLA-DR) T/B-cells
Time period of years
Ref. 32-33
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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.
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Summary-1

• Sjogrens syndrome represents the interface of
• Immune and exocrine secretory functions (dryness)
• Immune and neural function (neuropathy/cognitive)
• Immune and hypothalamic-adrenal axis (endocrine)
• d) Autoimmune proliferation and lymphoma
• e) Lupus-like features of vasculitis and immune
  complex

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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.

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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.

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Treatment of Sjogrens in 2012Opportunities and
Challenges

• Treatment of Dry Eyes and Mouth
• Treatment of Extraglandular Manifestations--
• Lupus like symptoms-arthralgia, rash
• Neuropathy (central and peripheral)
• Cognitive and myalgia (fibromyalgia)
• Lymphoproliferative

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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

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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.

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Fibromyalgia The elephant in the Room
Fatigue Cognitive
Dry eyes and dry mouth
Nerve pain
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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.

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Cytokines alter pain perception
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(No Transcript)
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Brain Regions that May Modulate Pain and
Emotion1-4
Central Amplification of Pain from Eyes and
Mouth Regions Found on Functional
MRI
Both
Pain
Somatosensory Cortex
Insular Cortex
Prefrontal Cortex
Thalamus
Hippocampus
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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_at_mac.com

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The Bodys 2 Distinct But Interconnected Immune
Systems

• ACQUIRED

INNATE
HLA-DR4dependent T cells respond to peptide
antigens and generate memory cells
HLA-DRindependent Dendritic cells respond to
specific structures found on bacteria and
apoptotic Products (Toll receptors)
Lymphyocytes (Type 2 interferon signature)
Dendritic Cells (Type 1 interferon signature)
Beutler B et al. Blood Cells Mol Dis.
199824216-230.