Transcript Treatment Strategies in the management of Sjogren’s Syndrome

Sjogren’s Syndrome:
Pathogenesis
and New Directions for Therapy
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiMED Medical Center
La Jolla, California
[email protected]
Why has it been so hard
to develop successful therapies
for Sjogren’s or SLE?
Roadblocks to
Treatment of Dry Eyes and Dry Mouth
• Problems with study design
• Poor correlation with objective clinical and
laboratory values
• Concept of “functional circuit” not
recognized by immunologists or Pharma—
while it is the basis for neurologists and
pain therapy
Therapy
for
Extraglandular Manifestations
• Lupus-like vasculitis (immune complex)
• Aggressive lymphocytes (interstitial
pneumonitis, nephritis, lymphoma)
• Responds to rituximab or
cyclophosphamide
• This is area where usually can show benefit
with rituximab and other therapies
Goals for Therapy
Fatigue, Myalgias and Cognitive Impairment
• This is the “holy grail” of neuro-immunology to solve in
the next decade.
• Flu-like symptoms, “ jet lag,” or after treatment of hepatitis
C with IFN.
• We have animal models from duloxetene (now for back
pain) or modafinil (jet lag)
• Molecular targets such as mTOR.
Fatigue and
Cognitive Impairment
• Much more common in SS or SLE
than in RA What is that telling us about pathogenesis?
• Involves the neuro-endocrine-immune axis
associated with “stress” response
(hypothalamic-adrenal axis)
which we must add
to innate and acquired responses as targets
Sjogren’s Syndrome[1] Incidence: is only 0.5% of the global population
[2] About 90% of S.S. patients are FEMALE
Considered an “unmet need” by FDA and ACR
Strong support from patient groups and Congress
(key in approval of SLE therapies such as belumimab)
“QUALTITY OF LIFE”SS patients equated
the impact of DRYNESS from SS
on their quality of life
at same level of limitation as patients with
moderate angina (chest pain).
They are willing to GIVE UP
2 YEARS OF LIFE to not have SS !!!
Factors NOT generally considered or able
to be measured with blood / lab tests:
• “DISABILITY” that is most commonly due to
fatigue and cognitive impairment
• “LIMITATIONS” on Activities of Daily Living
(ADLs):
 dry eyes -- limits work--- (especially on computer)
 dry mouth -- interferes with sleep, occupational and
social interactions (talking, eating)
 extra-glandular manifestations -(see next slides)
• “Financial and emotional expense” of frequent need
for
“artificial tear” drops and dental decay treatment
EYE DRYNESS results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s Syndrome
The upper lid
literally sticks to the
Epithelial surface
and pulls surface
mucin layers off.
The Rose Bengal
dye retention test
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” (dry mouth)
with dry tongue
Sjogren’s Syndrome-caused
Cervical Dental Caries (cavities)
In order to understand
why therapies used in RA
are not “effective”
We need to review the “functional” circuit
which is recognized by Ophthalmologists
and Pain Specialists (i.e., phantom pain)
but not by rheumatologists
Normal Tearing or Salivation Secretion
requires a functional unit
5. gland
water
nutrients
hormones
4. blood vessel
water
mucin
protein
1. mucosal surface
afferents
efferents
2. lacrimatory
or salivatory
nuclei
3. cortical
input
central nervous system
Sjogren’s Syndrome affects functional unit
ocular surface
(cytokines, MMP, growth factor)
Gland
cytokines,
Autoantibodies
metalloproteinases
Cholinergic
efferents
lymphocytes
blood vessel
Chemokines
CAMs
iNOS
adrenergic
central nervous
system
(HPA axis)
Pathogenesis
current interest usually concentrates
on salivary biopsy
as the model of inflammation.
Misconceptions:
a)The salivary gland is not destroyed in “dry” patients,
but
only about 50% of the ducts/acini are destroyed.
b)The gland destruction is only mildly progressive with time
(although symptoms may progress).
c)Although subtle markers of biopsy predict lymphoma—this
will not be “measurable” during clinical study.
In Sjogren’s Syndrome,
many acini and ducts are spared
Sjogren’s
Normal
In Sjogren’s Syndrome
1. The residual glandular cells are
partly paralyzed by the local
immune reaction.
2.
The sensation of dryness
is a cortical event
and poorly correlates with tear film
(even with topical anesthetic).
Sensation of dryness
at level of gland and at CNS
• Neural fibers (PGP 9.5) still innervate residual
gland including sympathetic and VIP/substance P
Normal Tearing or Salivation
Secretion requires a functional unit
5. gland
water
nutrients
hormones
4. blood vessel
water
mucin
protein
1. mucosal surface
(topical anesthesia)
afferents
efferents
2. lacrimatory
or salivatory
nuclei
3. CNS
central nervous system
Reasons for Glandular Dysfunction
in Sjogren’s
1.
Cytokines inhibit neural transmission—
(as we know from multiple sclerosis).
2.
Metalloproteinases destroy matrix
necessary for gland orientation.
Reasons for Glandular Dysfunction
in Sjogren’s
Cytokines (esp. IL-1, TNF)
interfere with release of Ach/VIP
from nerve endings and
response to Ach by glandular cells
Steps in Pathogenesis
• Homing to specific tissues (glands)
• Production of autoantibodies
• Pathogenesis of salivary gland lesions
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.
Lymphocytes have surface “homing receptors”
when generated in node or marrow.
Interfere with homing
(obligate apoptosis if not bind “addressin”)
• Natalizumab (Tsabri)- cell adhesion a4-integrin
• Odulimomab (ICAM, CD54, LFA-1)adhesion and migration
• Fingolimod (Gilenya)sphingosine-1 receptor
• CD22 (Epratazumab)
Time course of autoimmune response*
1. Genetic factors predispose to Sjogren’s
2. Environmental factors such as a viral infection may lead to formation of
autoantibodies.
2. Antibodies precede disease.
3. However, presence of antibody does not necessarily 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
Gene expression profiling of minor salivary glands clearly distinguishes
primary Sjögren's syndrome patients from healthy control subjects
Arthritis & Rheumatism
Volume 52, Issue 5, pages 1534-1544, 5 MAY 2005 DOI: 10.1002/art.21006
http://onlinelibrary.wiley.com/doi/10.1002/art.21006/full#fig1
The main cytokine targets match those
identified in genome wide screens*
HLA-DR (T-cell), CTLA and IFN-g
NF-K /IkB
Homing receptor (CXCR5)
Type I IFN –IRF5, STAT4, TLR3/7/9 and pkR
(cytoplasmic sensor)
• B-cell activation –BLK, BAFF, IL12, and A20 (TNFAIP3)
•
•
•
•
*
Most of these targets do not map to the encoded protein but to upstream sites of RNA
transcription that are not translated (presumed epigenetic sites such as methylation)
Now we have methylation maps
These methylation maps show different targets
Previously Studied in SS
•
•
•
•
Anti-CD20 –glandular and extraglandular
BAFF (Blys)-ACR 2012 abstracts*
Abatacept (CD40 L)-ACR 2012
Allogeneic mesenchymal cells-ACR 2012
abstracts and article in Blood
•
www.rheumatology.org/wren/acrsearch.asp?zoom_query=acr%20abstracts%2
02012&st=nocache&actn=search&dt=12/24/2012%202:29:59%20P
Other Inhibitors of IFN
a. Initial trials of anti-type 1 IFN
had infusion reactions and only
modest efficacy
b. Medi 546 (type 1 IFN-R antagonists)
now in phase 1 (scleroderma)
and juvenile SLE phase 2 trial
Rituxan may be back
with Cytoxan
for SLE….
and Sjogren’s
The true unmet need
is the fatigue and myalgias—
--this is the cause of disability-a) similar to influenza symptoms
b) after hepatitis C, patients get interferon therapy
c) “jet lag” symptoms
d) depression
All of these have been studied, but therapeutic models
not applied to Sjogren’s syndrome
Neuropathy
• Poor correlation between symptoms and
objective findings:
– Eye pain- does not correlate with tear flow;
– Mouth pain- does not correlate with saliva;
– Peripheral neuropathy- does not correlate with
nerve biopsy;
– Cognitive- does not correlate with acute phase
reactants.
Fibromyalgia:
The elephant in the room
Fatigue
Cognitive
Dry eyes and
dry mouth
Nerve
pain
Transcriptional Profiling Experiment
1. Challenge mice. Sacrifice 1 or 3 hrs later.
Physiological
LPS
10 µg/mouse
IP
Psychological
Restraint
30 minutes
50 ml tube
Fos immunoreactivity
Saline
LPS
Restraint
Organization of the Paraventricular Nucleus
Target
Signature
Function
Median
Eminence
CRF
ACTH secretion
Posterior
Pituitary OT
AVP
Pressor, antidiuretic
Lactation, parturition,
Autonomic
CRF
AVP
OT
Transmitter/modulators
in central autonomic
pathways
Similar pattern of
Fos-ir in PVH neurons
in response to distinct stressors
Emotional
Physiological
Therapeutic Models
• We need to cross-screen therapeutic agents
in our depression and pain models.
• There are shared pathways— such as
rapamycin (mTOR) that have been used in
models of depression (AKT pathway).
Thrombospondin modulates TGF-b (anti-inflammatory)
(Tsp-/Tsp- mouse has Sjogren’s)
NGF
TGFb
IL-1b
TNF
Monoclonals with drugs attached
Time to mix immune modulator with
neuromodulator
How about an anti-cytokine with a neuro-modulator
attached ?
 Such as anti-lymphocyte plus cevimeline
 Such as anti-ICAM plus duloxetene?
 Such as anti-cytokine plus inhibitor of TGF-b
or up-regulator thrombospondin?
Novel therapies
Methylation and histone acetylation
patterns— significant changes in Sjogren’s
gland
including the diurnal variation in saliva
Micro-RNA regulation—a realistic
possibility due to accessibility of eye and
mouth to topical
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
The way we perceive pain and
suffering is under our control