Pathogenesis of Sjogren’s Syndrome

1
Pathogenesis ofSjogrens Syndrome

• Translating Basic Sciencefrom Bench to Bedside

2
Sjogrens 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)
• Out of pocket expense of artificial tears and
  dental decay

3
Background-1

• Sjogrens 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-2The 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 therapyincluding TNF, BAFF and IL-6
  inhibitors, steroids, traditional DMARDs 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 - 2The two arms of the immune
system mutually interactin the initiation and
perpetuation of Sjogrens 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 motifs
• ? 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 3The 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

5. 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
4. Stimulation of blood vessel
9
In Sjogrens 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
10
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
11
In Sjogrens syndrome

• The residual glandular cells are paralyzed by the
  local
• immune reaction.
• Even though the acini/ducts
• are 50 present, their innervations and their
  receptors
• for neurotransmitters are present.

12
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.
13
We need to keep in mind that the gland is not
destroyed but appears paralyzed,the release
of cytokines hasled to dysfunction
14
This may help us understanda) the functional
circuit analogy may also apply to neuropathic
pain(poor correlation with nerve biopsy)b)
symptoms of dry eyes and dry mouth that do not
correlate with either tear or saliva flow
measurements
15
Or Fibromyalgia(Central Sensitization)where
symptoms of fatigue and cognitive (executive)
function do not correlate with our acute phase
reactants or MRI scans
16
Take home Clinical Lessons

• When we see a dry eye, when do we need to
  immediately refer to Ophthalmology?
• What are the warning signs for lymphoma when we
  see a swollen parotid gland?
• What should we do with the patient who has
  symptoms of neuropathy or fatigue?

17
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
18
For Routine Dry Eye

• Do not use preserved tears more than 4 times a
  day
• Learn to mix and match
• No Lasik surgery and care with blepharoplasty
  (exposure keratitis)
• Use of lubricants at night and lid scrubs in AM
• Restasis may be useful
• Punctal Occlusion
• Lotemax (a soft steroid) may be used together
  with Restasis for 2 wks

19
But be on the look out for conditions that
require immediate Ophthalmologic
EvaluationCorneal Abrasion (fluorescein)
20
Ulcerative keratitis(in patient given broad
spectrum antibiotic plus anesthetic)
21
Scleritis (vasculitis)
22
Non-ulcerative keratitis
Herpetic keratitis (slit lamp-fluorescein)
dendrites
23
What are the particular oral needs of the SS
patient

• A dry mouth is not necessarily a painful mouth
• Yeast infection in the mouth is erythematous
  candidiasis-esp. on hard palate and buccal
  recesses
• look for angular cheilitis and erythema under the
  dentures
• Fissured tongue and loss of papilla
• Poor correlation between symptoms and flow rates

24
Burning Mouth Syndrome

• Mouth symptoms are out of proportion to the
  objective dryness
• May be a localized form of neuropathy
• This may respond to a mouth rinse with (klonepin
  .5 mg in 2ml mylanta) for 2 minutes bid
• May be due to oral yeast infection

25
Severe Xerostomia with dry tongue
26
What are the particular needs at time of dental
visit

• Frequent hygiene visits
• Avoid full veneers that cover caries
• Avoid amateur tooth whiteners (at malls)
• Use of fluoride topically and by tray
• Use of MI Paste by Oral Hygienist
• Avoid Sugar and acidic beverages

27
Sjogrens Syndrome- Cervical Dental Caries
28
SS has lymphoproliferative propertiesit lies
on the border between autoimmunity andlymphoma.
29
Sjogrens Syndrome with parotid enlargement
indicates lymphoproliferative tendency
30

• 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
31

• In patients with persistent parotid swelling
  despite a brief trial of steroids/antibiotics,
• particularly unilaterally for over 6 wks or recur
  when taper steroids
• Enlarged cervical node next to parotid
• B-symptoms such as fever and weight loss
• Low threshold for needle biopsy to rule out
  lymphoma

32

• Since over 60 of these lymphomas are MALTs
• they may be very responsive to B-cell depletion
  (Rituxan) as is published
• we still favor Cytoxan plus Rituxan in MALTs
• If your oncologist wants to give CVP-R, go very
  light on the vincristine due to increased
  susceptibility of neuropathy

33
Extraglandular Manifestations of Sjogrens
Syndrome
Is Sjogrens syndrome just SLE with 4
criteria? It is best to think of SLE as a
disease mediated by antibody and immune complex
damage It is best to think of Sjogrens as a
disease mediated by cell infiltration into
tissues There is a great deal of overlap, but
also differences
SSS
SS
SLE
34
Sjogrens vs. SLEextraglandular

• The rash of leukocytoclastic vasculitis vs.
  hyper-globulemic purpura
• The lung manifestations of pleurisy vs.
  interstitial pneumonitis
• The renal manifestations of glomeruloneprhtis vs.
  interstitial nephritis
• The increased risk of lymphoma

35

• However, SS and SLE are more similar than
  dissimilar
• The genetics of SS are remarkably similar to a
  subset of SLE (i.e.. HLA-DR3)
• The pattern of auto-antibodies are similar,
  including SS-A in SLE patients
• Most importantly, the response to therapies are
  similar

36
Fibromyalgia The elephant in the Room
Fatigue Cognitive
Dry eyes and dry mouth
Nerve pain
37
Our most difficult problems

• Neuropathyperipheral and central
• Chronic fatigue and vague cognitive impairment
• Lymphoproliferation
• Accelerated cardiovascular complications.

38
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.

39
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.

40
Cytokines alter pain perception
41
(No Transcript)
42
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
43
Fibromyalgia

• We have found the combination of low dose
  cymbalta (30-60) plus Lyrica 75 most useful and
  best tolerated
• More cymbalta and GI intolerance
• More Lyrica and weight gain

44
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.

45
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

46
(No Transcript)
47
Treatment of Sjogrens in 2010Opportunities 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

48
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.

49
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 Sjogrens may
  provide insight into fibromyalgia

50
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
51
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
52
New Approaches to Dryness-2Oral 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

53
Novel methods of water conservation
New Approaches to Dryness-3

• 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)
54
Electrical Stimulation with intra-oral
deviceStrietzel et al (2011) Arth Rheum pg.
63Abstract 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.
55
Reminiscent of Electrical Stimulation (Salitron)
in 1980sStellar (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

56
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.

57
Systemic Therapies-1

• Traditional DMARDs- alone and combination.
• Hydroxychloroquineworks 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

58
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).

59
Systemic Therapies-2Leflunomide 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.

60
Take home lessonfor 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.

61
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 steroidslotemax-like for
  effect on NFK-b this was the basis of p38 map
  kinase
• Novel IKKB inhibitors that lack effect on weight,
  bone, etc.

62
Biologics and Cytotoxics

• Biologic Agentsthe 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 cyclophosphamidealthough 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 diseasewe must reset
  the repertoire using cyotkines and growth
  factors. There will probably be a role for
  cyclophosphamide in this process.

63
Available biologic therapy for Sjogrens-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

64
Rituximab (anti-CD20 antibody)-numerous reports
in Sjogrensthat 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.

65
Rituximab failed the two pivotalFDA trials in
lupusboth 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).

66
Rituximab Most Consistent Rolefor Hematologic
Features in SS lymphadenopathy,
pseudolymphoma, thrombocytopenia
mixed cryoglobulin low grade lymphomaAs 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.
67
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.

68
Important lesson about biologicsfrom 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.

69
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.

70
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).

71
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.

72
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.

73
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 Ly2127399 (Lillys
  anti-BAFF)(membrane and free)
• Bortezomib (protesome inhibitor)
• Refs 60-61 and clinicaltrials.gov

74
Additional Trials

• Raptiva (stopped)
• Thalidomide (stopped)
• DHEApast NIH trial vs. SLE trial
• Mycophenolic Acid
• Rituxan and biogeneric

75
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
76
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 Sjogrens.

77
Problem will again be the risk of PMLa 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.