1. Pathogenesis of Sjogren’s Syndrome:
Translating Basic Science from “Bench to Bedside”

2. Sjogren’s Syndrome Increased mortality risk, particularly due to
lympho-proliferative complications
Quality of life- equated with moderate angina
“Disability” predominantly due to fatigue and cognitive
“Limitations”:
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

3. Background-1 Sjogren’s syndrome represents the interface of:
Immune and exocrine secretory functions (dryness)
Immune and neural function (neuropathy/cognitive)
Immune and hypothalamic-adrenal axis (autonomic)
d) Autoimmune proliferation and lymphoma
e) Lupus-like features of vasculitis and immune complex

4. Background-2 The Danger Signal
When we get “flu symptoms”
of arthralgia, fatigue, cognitive dysfunction—
it is a result of the cytokines/neurotransmitters
released by the innate immune system.
When these reactions persist due to a vicious cycle perpetuated in genetically predisposed individual by the acquired immune system,
the result is autoimmune disease.

5. Pathogenesis: Take Home Lessons-1
Innate and Acquired Immune Systems are targets for current therapy—including TNF, BAFF and IL-6 inhibitors, steroids, traditional DMARD’s and new oral agents (Jak and syk inhibitors).
Functional circuit that controls immune and neural function comprises the new “frontier” for therapy from fibromyalgia to depression. The functional circuit is the link between cytokines and symptoms.

6. Take Home Lesson - 2 The two arms of the immune system mutually interact in the initiation and perpetuation of Sjogren’s Syndrome
Acquired System
Innate System
 (Adaptive, immediate) - HLA independent
 Dendritic cells
 Cytokines-particularly
 Type I interferon
 Interferon-gamma
 BAFF, IL-6, IL-17
 Complement, CRP
Sensors of the innate system
 Toll receptors (TLR)-pathogen motiffs
 DAMP (damage recognition patterns)-apoptosis
 RIG-1 (retinoid inducible genes)
 NOD/Card receptors-more than in colitis
 (HLA-DR)-memory
Traditional T-cell and
B-cell and their cytokines
HLA-DR association
with autoantibody
production
Target of drugs such as
DMARDs and certain
biologics

7. Take Home Lesson 3: The Functional Circuit (Cytokines are not enough)
Control of tears or saliva flow are complex processes that involve both afferent nerve pathways that go to the midbrain and efferent nerves that modulate glandular function. The midbrain signals are influenced by the cortical outflow and the hypothalamic axis.

8. Normal tearing or salivation secretion requires a functional unit
water
mucin
protein
Ocular or oral surface
irritation
4. Stimulation
of gland
Nerves on mucosal
water
nutrients
hormones
3. Cortical
Outflow
Tracts
and
HPA
Afferent nerves
2. Midbrain of
central nervous
system
Lacrimatory or salivatory nuclei
3. Stimulation
of blood vessel

9. The functional circuit involves known neural connections to the brain
*Pflugfelder SC, et. al. Dry Eye and Ocular Surface Disorders. NY: Dekker, 2004.

10. ocular and oral dryness
In Sjogren’s syndrome, the release of Ach and VIP
by efferent nerves to the glands
--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

11. In Sjogren’s, only 50% of the acini and ducts are destroyed
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
Normal
Sjogren’s

12. In Sjogren’s syndrome
The residual glandular cells are paralyzed by the local
immune reaction.
Even though the acini/ducts
are 50% present, their innervation and their receptors
for neurotransmitters are present.

13. 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.

14. Pathogenesis Take Home Lesson- 2
Although many complex interactions take place in the salivary gland, a characteristic type I interferon gene signature is noted repeatedly.
The relationship of autoantibody to SS-A/SS-B and type I interferon signature has recently been suggested.
This links our blood tests (SS-A) and clinical features.

15. IFN Type I in salivary gland suggests a role in Sjogren’s Syndrome
SS SG biopsy with type I
IFN gene profile
NML
Non-SS sicca
SS SG biopsy with type I IFN

16. Take home lesson-3 Homing receptors determine both glandular and extraglandular features
Salivary glands normally lack lymphocytes, so their mere presence in
an extraglandular tissues imply a lymphocyte aggressive process.
Homing to the gland tissue is due to specific receptors/ligands controlled by chemokines/cytokines.
Retention of lymphocytes in the tissue is due to specific ligands.
Their apoptosis or expansion is regulated through Fas pathways
that are modulated by cytokines and bcl-2

17. Pathogenesis: Take Home Lessons-4
Extraglandular manifestations are determined by lymphocyte homing to tissues-- factors that govern their retention in tissues and their apoptosis.
Factors governing their clonal expansion and lympho-proliferation lead to lymphoma-derived from B-cells themselves, T-cells, and dendritic cells.

18. 1. Tissue Homing/Retention of lymphocytes is the key process for accumulation of glandular infiltrates, as virtually no mitotic cells are seen in the gland. 2. Subsequent migration from gland into efferent lymphatic defines re-circulating memory lymphocyte pool.

19. The endothelial cells attract T-cells by
ICAM’s and Chemokines
Sjogren’s Lip Biopsy B

20. The endothelial cells release B-cell chemo-attractants
Ref 63

21. Endothelial cells attract dendritic cells
to home to the gland.

22. Take Home Points for Homing Receptors:
Expressed by salivary glands in NOD.scid mice, so expression is independent of cytokines released from the lymphocytes.
b) Thus, the story of Sjogren’s syndrome is
not a poor salivary gland that is “beaten
up” by the lymphocytes-- but that the
glands participate in the homing and
pathogenesis of inflammatory cells and
subsequent inflammation.

23. c) The problem with blockade of homing receptors
(whether Tsabri or Raptiva) has been the emergence
of rare but devastating problems due to reactivation
of papilloma viruses (such as JC) with clinical PML
(progressive multi-focal leukoencephalopathy).

24. Pathogenesis Take Home Lesson 4 SS has lymphoproliferative properties— it lies on the border between autoimmunity and lymphoma.

25. Sjogren’s Syndrome – with parotid enlargement indicates lymphoproliferative tendency
MRI not used much for diagnosis of SS itself but of value in investigating causes of persistent salivary gland swelling. However with the increasing availability of scanners, and emerging evidence from Berlin [Vogl et al]and Japan [Izumi et al], we may see this non-invasive technique being used more frequently for diagnostic purposes

26. Risk factors for lymphoma
Germinal centers on minor salivary gland biopsy
Low complement C4
MGUS (esp. IgM-K with RF activity) and mixed cryoglobulin
The T-cells and dendritic cells drive B-cell clonal expansion, particularly driven by BAFF, until a B-cell clone escapes to become a lymphoma.
Germinal Centers in Minor SG Biopsy

27. This provides a rational of understanding for 1
This provides a rational of understanding for 1. anti-CD20 (rituximab) 2. anti-BAFF and anti-TACI 3. anti-CD22 antibody therapies

28. Overview of the steps in pathogenesis that help explain role of gender (TLR receptors) autoantibodies (anti-SS A) interferon-Type I signature HLA-DR association

29. SS: Hormonal Factors (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 prolactin hormonal
regulation.

30. Time course of autoimmune response. 1
Time course of autoimmune response* 1. Environmental stress is interpreted in context of genetic factors. 2. Antibodies precede disease. 3. Presence of antibody does not mean disease.
Innate
Immune system
(Toll receptor)
Auto-
antibodies
Environmental
Stress
(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)
Genetic
Factors
(including sex)
(HLA-DR)
Disease
Manifestations
Acquired
Immune system
(HLA-DR)
T/B-cells
Time period of years
Ref

31. Genetic Predisposition in SS to Type I Interferon
In genome wide screens, association of IRF5 alleles and Stat 4, with predisposition to development of SS* * Refs 36-38

32. Other Factors in Pathogenesis
Gender - SS is a predominantly a disease
of women.
Onset and increase of dryness with
menopause.
Increased risk of Klinefelter (XXY) in male SS*
—Toll receptor translocation (BXB model).
Aromatase knockout mouse gets SS.
RbAp48--estrogen dependent apoptosis.
DHEA and CRISP-role in glandular processing.
* Refs 34-40

33. At this point … I want to stop for questions and see if you
would like to break or stay for new
approaches to therapy
Thanks again for inviting mel.

34. Treatment of Sjogren’s in 2010: Opportunities 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

35. Take Home Points-1
Topical therapy of dry eyes and dry mouth: new targets include water transport, mucins, and topical small molecules such as jak 3.
Dry mouth symptoms may be “burning” mouth and require treatment as a local neuropathy.

36. Take Home Point-2
Poor correlation of symptoms and objective findings of both dryness and neuropathic symptoms.
This poor correlation is the greatest challenge since it involves cortical perception of discomfort
The neuro-endocrine circuit in Sjogren’s may provide insight into “fibromyalgia”

37. Take home points-3 Systemic Manifestations for lupus like symptoms
DMARDs
Hydroxychloroquine
Methotrexate
Leflunomide
Small molecules-Jak3 and Jak ½
Filomodulin (MS approved)
Biologic Agents
Anti-CD20 rituximab and new variants
Anti-BAFF (Benlysta)
Anti-CD22 (Eprumazab)
Taci-Ig and
ICOS
Homing receptors

38. New Approaches to Dryness
Topical Ocular Dryness
“smart artificial tears”
Mucin
Androgen
Micro-iRNA
Anti-IL-17*
Jak 3 inhibitor*
Metalloproteinase inhibitor
* Currently cyclosporin is water insoluble and irritating

39. New Approaches to Dryness-2 Oral Agents are better than pilocarpine or cevimeline
… since the gland is not destroyed but is paralyzed by cytokines and metalloproteinases
Improved secretagogues
(new muscarinic agents in trial)
Anti-cytokine therapy has
modest effect only in patients
with early disease

40. Novel methods of water conservation
New Approaches to Dryness-3
Novel methods of water conservation
1. Transport water across the conjunctiva (diquafasol)
p2Y2 purine receptor agonist
2. Decrease evaporative loss
(muc 3, muc 5A, lipid)
Decrease water reabsorption
through membranes of eye
by blocking trans-epithelial salt
(and water) channels that drain
orbit (compound P552-02)
p2Y2 receptor directly transport water across conjunctiva
Tear film
Membranes at the base of the orbit are a major site of ‘water exit” (in addition to the puncta)

41. Electrical Stimulation with intra-oral device Strietzel et al (2011) Arth Rheum pg. 63—Abstract misleading
Results: “The active intervention performed better than sham for some secondary outcome measures for dryness frequency. No statistical significance for the parameters oral discomfort, sleeping difficulty, resting salivary flow rate, and stimulated salivary flow rate.”

42. Approved by FDA as a “device” Denied by insurance due to “efficacy”
Reminiscent of Electrical Stimulation (Salitron) in 1980’s Stellar (1988); Daniels (1992)
Approved by FDA as a “device”
Denied by insurance due to “efficacy”
Price precluded use by patients
About the same benefit as use of a vibrator (used intra-oral) or electric toothbrush to stimulate tongue and buccal mucosa
Importance of mechanical stimulation, including the use of lozenges

43. The standard joke about therapy
Rheumatologists only have one drug: steroids.
The training of a rheumatologists is how to get the patient to a lower dose of steroids or off them entirely.

44. Systemic Therapies-1 Traditional DMARDs- alone and combination.
Hydroxychloroquine—works on “antigen processing”
by raising pH of antigen loading compartment.
Hydroxychloroquine is a weak diprotic base that diffuses into compartment for loading and raises the pH of the “endosome.”
This effect prevents the “loading” of low affinity (autoantigens) onto nascent DR molecules.
Also, affects the ability to bind to Toll receptors in the lysosome.
Using this model, new through-put screening of new and better drugs

45. Systemic Therapies-2
Traditional DMARDs- What is new with methotrexate?
Alone or in combination with hydroxychlorquine to taper steroids;
Methotrexate polyglutamate may predict efficacy and toxicity-however, methotrexate polyglutamate levels are still in trial in SLE and SS;
Most exciting are the reports of new SNPs to predict methotrexate responsive patients in RA;
(all the SNPs are in the de novo adenosine pathway).

46. Systemic Therapies-2 Leflunomide and mycophenolic acid- both have mechanism of action that are similar and analogous to methotrexate
Methotrexate works on de novo synthesis for purine ribonucleotide pathway.
Leflunomide and Mycophenolic acid on de novo pyrimidine ribonucleotide pathway.
These ribonucleotides serve as energy source (mostly for
glycosylation) that is required for cell division.
Unless, adequate rUMP, impaired G1-S transition.

47. Take home lesson for Methotrexate, Azathioprine, Leflunomide, mycophenolic acid
All work by inhibiting synthesis of ribonucleotides that serve as an energy source (de novo synthesis pathway) required for G1-S transition of maturation.
This pathway links p52 and p21 driven apoptosis; p52 is the “sensor” for adequate ribonucleotide level.
Ribonucleotide synthesis as an energy source for cell membrane synthesis and glycosylation.
In future, it is likely that we can use SNPs to predict response to these agents based on their enzyme polymorphisms.

48. Systemic Therapies-3 Traditional steroids:
Prednisolone and methylprednisolone)—cheap and
work but side effects
In general, the issue with steroids is the dose
(less than prednisone 7.5 and duration of therapy)
Development of “soft steroids”—lotemax-like for effect on NFK-b ; this was the basis of p38 map kinase
Novel IKKB inhibitors that lack effect on weight, bone, etc.

49. Biologics and Cytotoxics
Biologic Agents—the new “holy target” based on success in RA; however, biologics have been disappointing in SLE and SS (we will deal with these later in talk).
Cytotoxics such as cyclophosphamide—although we worry about cyclophosphamide, we need to ask how much is actually justified if we use carefully and limit cycles.
We worry about marrow depletion but yet hematologists use it to mobilize “stem cells” into the periphery.
In order to “cure” immune disease—we must reset the repertoire using cyotkines and growth factors. There will probably be a role for cyclophosphamide in this process.

50. Available biologic therapy for Sjogren’s-1
TNF antagonists- one initial report of success with infliximab*
Repeat studies not replicate early success
Repeat infliximab study (multi-center, more patients)*
Etanercept*
*Refs 43-47

51. Rituximab (anti-CD20 antibody)-numerous reports in Sjogren’s that are multi-center and controlled
B-cell depletion efficient in periphery;
Decreased lymphocytes in gland biopsy;
Surprisingly, little change in serum BAFF or IgG levels;
Well tolerated.

52. These trials were poorly designed. The steroid dose was too high.
Rituximab failed the two pivotal FDA trials in lupus— both renal and non-renal
These trials were poorly designed.
The steroid dose was too high.
The patients were too heterogeneous.
The drug worked, but so did the placebo (standard of care).
The finding of several cases of PML (progressive neurodystrophy due to JC virus).

53. Rituximab Most Consistent Role for Hematologic Features in SS
Rituximab Most Consistent Role for Hematologic Features in SS *lymphadenopathy, *pseudolymphoma, *thrombocytopenia * mixed cryoglobulin *low grade lymphoma As it will not have “FDA label,” it will be an off-label use, and expense in US will limit its use-- as insurance will not cover.

54. Rituximab Treatment
Only small changes in tear/saliva flow and only in patients with early disease;
Changes in salivary gland biopsy with improvement in foci score;
B-cell depletion as expected;
Change in T-cell repertoire (CD25+ T-reg) in some patients.

55. Important lesson about biologics from Rituximab
When you deplete B-cells (rituximab):
Create an excess of circulating BAFF in comparison to the number of B-cells that bear BAFF-Receptor;
This excess of ligand stimulates a round of cell division not only of B-cells but of B-cells;
Any round of cell division leads to activation induced cell death (AICD) and opportunity to re-shape the repertoire.

56. The “cure” of autoimmune disease
will depend on changing the repertoire--
T-regs to modulate auto-immune cells;
Alteration of homing receptors;
Regeneration of damaged target organs.

57. Humanized anti-CD20 (ocrelizumab)
Higher Affinity for B-cells;
Had Fc receptor for complement and B-cell depletion;
Clinical trials halted due to increased infection (although mostly at non-US sites).

58. Other Biologics-1 Anti-BAFF (Benlysta) antibody;
Approved for SLE by FDA;
The SS subset of SLE (SS-A) did not show significant improvement compared to SLE cohort;
Although the Benlysta subset did better than with no treatment, the patient and physician Global Assessment was not significantly different from placebo and marginally different than low dose.

59. Other Biologics-2 Anti-CD22 (Epratuzumab)—another B-cell marker;
Initial clinical trials in SS (and SLE) plagued by production of a uniform product (problems in glycosylation), so 6 different lots needed with interruption of protocol;
New Drug Manufacturer and preliminary studies indicate safety;
Any FDA approval for SS will require increased saliva and tears. Expect at best, results similar to rituximab.

60. Other therapies in trial (biologic)
Anti-CD22 antibody: initial results inconclusive and repeat trials in progress*
Antibody to IFN-a (Medi 545) in SLE*
(Dan Wallace at ACR (2007) and recruiting in Japan)
3 Antibody to type II (gamma) IFN (fontolizumab)
Antibody to BAFF-R, April and TACI-Ig*
Benlysta (free BAFF) and Ly (Lilly’s anti-BAFF)(membrane and free)
Bortezomib (protesome inhibitor)
*Refs and clinicaltrials.gov

61. Additional Trials Raptiva (stopped) Thalidomide (stopped)
DHEA—past NIH trial vs. SLE trial
Mycophenolic Acid
Rituxan and biogeneric

62. Fingolimod- a novel approach
The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors
Lymphocyte is retained in the lymph node until the sphingosine ligand is “removed”
Stromal cell has
Sphingosine receptor

63. Fingolimod-2 (recently approved for multiple sclerosis)
It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for auto-immune responses in multiple sclerosis, and was originally proposed as a anti-rejection medication indicated post-transplantation.
It has been reported to stimulate the repair process of glial cells and precursor cells after injury.
Fingolimod has also been reported to be useful in murine lupus and Sjogren’s.

64. Problem will again be the risk of PML— a rare but devastating complication
May be acceptable in life threatening diseases such as multiple sclerosis;
Unclear if the FDA will approve such drugs for “quality of life” issues such as dryness or fatigue;
The global assessment by physician and patient has been the huge limitation in FDA approval.

65. Fingolimod provides rationale for new therapies that interfere with homing
3. When the homing receptor encounters
vascular adhesive molecules,
the lymphocyte enters tissue.
CD4+
Blood
2. Lymphs migrate through blood
to tissues.
4. Pearl:
Failure to bind to homing
receptor in 72 hours
leads to obligate apoptosis
of the lymphocyte.
This is why we do not become
one large lymph node.
B cell
1. T- and B-cells have surface “homing receptors” when generated in node or marrow.

66. Caution: PML (progressive multifocal leukoencephalopathy)
Due to reactivation of polyoma virus (JC) in CNS
We have seen with agents: that alter homing:
Natalazumab (Tsabri)
Efalizumab (Raptiva),
and
B-cell depleting agents (Rituximab);
SS and SLE patients already handle polyoma poorly, as evidenced by higher frequency pap smear abnormalities.

67. Our most difficult problems
Neuropathy—peripheral and central;
Chronic fatigue and vague cognitive impairment;
Lymphoproliferation;
Accelerated cardiovascular complications.

68. 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.

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

70. 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.”

71. Pathophysiology of Pain
Cytokines
alter pain
perception
PURPOSE OF THE SLIDE
To introduce the concept of neuroplasticity that will appear throughout the presentation.
KEY POINTS
Neuroplasticity is defined as “the capacity of neurons to change their structure, function, or chemical profile.”
Plasticity may occur in multiple regions of the body during pain processing and contribute to the pain hypersensitivity observed in neuropathic pain. Thus, hypersensitivity is one expression of neuronal plasticity.
Activation, modulation, and modification are all forms of plasticity that may contribute to pain hypersensitivity.
REFERENCE
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:

72. Pathophysiology of Pain
PURPOSE OF THE SLIDE
To introduce the next section of the presentation, peripheral pain processing.
KEY POINTS
Nociceptors in the periphery act to transduce painful input (thermal injury, chemical injury or mechanical injury) into electrical signals.
Changes in peripheral nociceptors may contribute to altered pain transmission.
REFERENCE
Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, Schwartz JH, et al, eds. Principles of Neural
Science. 4th ed. New York, NY: McGraw-Hill; 2000:

73. 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
PURPOSE OF THE SLIDE
To show the brain areas that may be involved in processing pain signals and emotional responses to pain.
KEY POINTS
Ninety-eight studies were included in an analysis to determine commonly activated brain regions during pain conditions in normal subjects (68 studies) and in clinical pain subjects (30 studies) as imaged by hemodynamic methods including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Six brain regions were consistently and significantly activated across these studies: prefrontal cortex (PFC), insular cortex (IC), anterior cingulate cortex (ACC), primary somatosensory (S1) and secondary somatosensory (S2) cortices, and the thalamus.1
PFC: the lateral PFC has been activated in clinical pain conditions such as ongoing neuropathic pain, visceral pain, cluster headaches, and cold-allodynia in patients with neuropathic pain. Inferior (orbital) PFC may be activated by both painful and pleasant but not by neutral sensory stimuli, and is therefore thought to be involved in the processing of the affective aspects of sensory stimulation.2 Studies have also documented involvement in “executive functions,” such as working memory, decision-making, planning, and judgment.3
IC: the brain structure with the largest spectrum of cortical connections. Painful stimulation activates two distinct areas in the IC, one in the anterior-inferior part and a second in the posterior-superior part.2 This brain region also processes convergent information to produce an emotionally relevant context for sensory experience.3
ACC: one of the most frequently activated areas in pain imaging studies, exerts multiple functions in pain processing, and is most often associated with the affective component of pain. The ACC is also involved in pain anticipation, cognitive-attentional (specifically mid-cingulate portions), and motor responses to pain.2
Amygdala: performs a primary role in processing and memory of emotional reactions.3
Dysfunction within the hippocampus may contribute to inappropriate emotional responses to pain.4
There are a number of factors that influence whether or not a brain region is involved in pain processing: genetics, gender, and individual differences affect detection of activity in fMRI and PET studies.
The brain regions involved in processing pain depend on the type of pain experienced (extreme temperature, electrical shock, visceral).
Attentional (distraction), emotional, anticipation, and expectation states also affect pain processing
Other regions also involved in attentional processes associated with pain include the: S1, IC, thalamus, periaqueductal gray (PAG) and the orbiotfrontal cortex (within the prefrontal cortex).
A key distinction between acute and chronic pain is that the brain regions that are involved in interpreting chronic pain states appear to be activated differentially. In comparing the reaction to pain in normal subjects to clinical pain subjects, it was noted that the difference in degree of activation of these regions, except the thalamus, was statistically significant (p<.001).1
REFERENCES
Apkarian AV, Bushnell MC, Treede R-D, et al. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:
Casey KL, Tran TD. Cortical mechanisms mediating acute and chronic pain in humans. In: Cervero F, Jensen TS, eds. Handbook of Clin Neurology. Boston: Elsevier; 2006:
Charney DS, Nestler EJ, Bunney BS, et al, eds. Neurobiology of Mental Illness. 2nd ed. New York, NY: Oxford University Press; 2004.
Schweinhardt P, Lee M, Tracey I. Imaging pain in patients: is it meaningful? Curr Opin Neurology. 2006;19:

74. Take Home Lesson 1 1. Topical therapy and ability to stimulate
saliva or tears remains inadequate.
2. Treatment of extraglandular manifestations such as arthritis, rashes, hemolytic anemia, or lymphomas is rapidly improving.
3. The treatment of the neuro-endocrine manifestations (cognitive impairment and fatigue) remains inadequate.

75. 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

77. Rituximab (anti-CD20)*
Multiple studies of small number of patients and single center trials
General Conclusion--
a) useful in extra glandular manifestations including: mixed cryoglobulinemia pseudolymphoma (glands or lung)
-- hemolytic anemia and thrombocytopenia
b) results in tear/saliva flow not significant except in group of patients with early SS, where increase saliva was statistically increased but still modest improvement and biopsies showed improvement;
Among SLE patients treated with anti-CD20, SS-A subset responded less frequently and had shorter remissions;
After an NIH multi-center trial, company is not pursuing indication.
*Refs 47-59

79. How does the process start
How does the process start? There may be many different triggers in the genetically predisposed individual…
Defective apoptosis of glandular cells and clearance of these autoantigens;
Viral infection including EBV (in Caucasion and Japanese) and Coxsackie (in Greek patients);
Other viral infections (examples of Hep C, HIV and HTLV-1) can mimic SS;
Activation of endogenous retroviral fragments.
Ref 1

80. Role of Autoantibody: Anti-SS A
Anti-SS A antibody
(associated with HLA-DR3)
binds to SS-A
which is complexed to hYRNA
Antibody to SS-A
To the innate immune
system (dendritic cells),
hYRNA
is a double-stranded RNA
and looks like a viral RNA
that binds to
a specific Toll receptor.
hYRNA
(ds RNA)
SS-A

81. Salivary gland dendritic cells bind to the Fcreceptor to internalize the immune complexes containing SS-A/hYRNA
3. Toll 3 receptor is in located in the cytoplasm
1. Immune complex
antibody to SS-A
2. Fc- R
Plasmacytoid
Dendritic Cell
4. IFN
Type 1
hYRNA
(ds RNA)
SS-A

82. --The Vicious Cycle -- of innate and acquired leads to IFN type I (links genetic and autoantibody response)
6. B-cell
Anti-body response
Anti-SS-A
in HLA-DR3
pre-disposed female
5. IFN-a
4. Dendritic Cell
with
Toll Receptor
and Fc-g Receptor
3. Toll receptor
Fc-gamma R
SS-A/hYRNA
2. Immune
Complex
containing…
______
Apoptotic Cell

83. Pearl: Rituxan does more than deplete B-cells
Alteration of T-cell subsets (especially appearance of CD25+/FoxP3 T-regs) after treatment
indicates a role in “rebooting the computer.”
b) Lymphocytes remain present in the SG
biopsy, probably due to BAFF secreted by
dendritic cells.
*Refs 57-59

85. Typical Clinical Features of dry eyes, dry mouth and swollen glands

86. the surface epithelial surface mucin layers off.
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

87. For example IL-17 plays a key role in decreased secretion of water, proteins and mucin required in tears and saliva

88. Severe Xerostomia with dry tongue

89. Sjogren’s Syndrome- Cervical Dental Caries

90. The Body’s 2 Distinct But Interconnected Immune Systems
ACQUIRED
INNATE
HLA-DR4–dependent:
T cells respond to peptide
antigens and generate
memory cells
HLA-DR–independent:
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. 1998;24: