Download - Dr. Robert Fox

SJOGREN’S SYNDROME
Diagnosis and Therapy
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiMED Medical Center
La Jolla (San Diego), California
[email protected]
Learning Objectives - 1
1. List 4 benign manifestations of SS.
2. Identify at least 4 differential diagnoses
associated with symptoms that mimic
Sjogren’s Syndrome.
3. List 2 ways SS impacts health care costs.
Learning Objectives – 3
4. List 3 approaches to treatment of dry eye
and 3 considerations to be aware of
when treating dry eyes
5. List 3 approaches to treating dry and
painful mouth, and 3 considerations
to be aware of when treating it.
Questions we will explore
1. Is it SS or is it SLE?
1. Do we use traditional criteria (AmericanEuropean) or the new SICCA criteria?
1. How does SS overlap with the newly
described IgG4-related disease?
Overview of Therapy
addressed in this talk
•
•
•
•
•
Conservative Therapy Guideline
Avoidance of anti-cholinergic medications
How to choose artificial tears and saliva
How and when to use DMARDs
What is the story with biologics
Challenge
• How can we convey information about
treatment of dry eyes/dry mouth to our
patients in the limited time allowed in a
patient revisit?
This is a practical limitation that is very
important aspect of patient care.
•
All slides are available
on my website
as well as links to treatment
of common conditions
(oral yeast, etc.)
robertfoxmd.com
7
Background-1
Benign manifestations include:
1.
2.
3.
4.
Dry and painful eyes
Dry and painful mouth
Myalgias, fatigue
Impaired cognition
(executive function)—
trying to distinguish
“fibromyalgia” from “depression”
Patients would:
• Equate SS with impact similar to
moderate angina.
• Trade 2 years of “life expectancy”
to not have SS symptoms.
•Dry painful eyes are now the single most
common reason for visits to Ophthalmologist
SS-Related
Health Care Costs-2:
• Direct healthcare costs in Great Britain (NHS)
are second only to RA, and exceed SLE.
• RA £2693
(not including TNFs)
• pSS £2188
(not including OTC cost of
artificial tears or dental costs)
• Age Matched NHS Controls £849
Diagnosis
of
Sjogren’s Syndrome
• European-American Consensus
Criteria
• SICCA Criteria
The European-American
Consensus Criteria, 2002
• Symptoms of dry eyes and dry mouth
– Inability to eat a dry cracker without water.
– Water needed at bedside at night.
• Objective signs of dry eyes and dry mouth
(Schirmer’s test, tear break-up)
(Saliva flow)
Consensus Criteria, 2002
also called the American-European
Consensus Group Criteria (AECG)
• Evidence of a systemic autoimmune cause
for the dryness-– Positive anti-Ro (SS-A or SS-B antibody)
– Positive minor salivary gland biopsy (focus
score >1)
You need to be aware
• There is a recently proposed criteria called
the SICCA criteria (described below).
• The sudden introduction of a new criteria
has led to confusion in practice and
research.
SICCA Preliminary Criteria
(Shiboski, 2012)
•Requires 2 out of 3 criteria:
1. Positive Anti-SS A/B or ANA >320;
2. Ocular Staining Score >3;
3. Positive labial gland biopsy: focus
score >1.
There is about an 82% overlap
between the SICCA criteria and the
AECC criteria
Does it matter?
• Our outcome measure ESSDAI was based
on old AECC criteria.
• Literature search and prognosis are all
based on old AECC criteria.
• The 5 published studies comparing both
systems indicate IT DOES make a
difference.
Now in progress
• The SICCA criteria will need to be
modified
• Committees are now at work to form a new
consensus criteria.
Differential Diagnosis
Is Sjogren’s just SLE
with 4/5 SLE Criteria?
• Different antibody profile (anti-SSA/B)
are not criteria for SLE;
• SS is more organ specific –
(salivary/lacrimal gland)
and more lymphoproliferative.
Why is Sjogren’s not just SLE
with 4/5 Criteria?
1. Interstitial pneumonitis (not pleurisy),
interstitial nephritis (not
glomerulonephritis)
2. Higher frequency of lymphoma
3. Genome Screens support this with
Homing receptors found in SS but not
SLE (CXCR5)
Differential Diagnosis
of SS-1
• SLE-- many similarities to SS
• RA, Scleroderma, Dermatomyositis-called secondary Sjogren’s
• Primary biliary cirrhosis
• Fibromyalgia with incidental positive ANA
Differential Diagnosis of SS-2
•
•
•
•
•
•
Hepatitis C
HIV (AIDS)
Tuberculosis –extraglandular
Syphilis
Lymphoma with positive ANA
IgG4-Related Diseases-evolving spectrum
Differential Diagnosis of SS-3
• The antibody to Ro (SS-A) or La (SS-B) do
not fulfill criteria for SLE.
• Many older patients labeled with mild SLE
actually have SS.
• Many patients in Hematology clinic with
mixed cryoglobulinemia, hemolytic anemia
or ITP actually have SS.
Classification-1
Is Sjogren’s just SLE
with 4/5 Criteria?
• Different antibody profile (antiSSA/B)
are not criteria for SLE;
• SS is more organ specific –
(salivary/lacrimal gland)
and more lymphoproliferative.
Classification-2
Why is Sjogren’s not just SLE
with 4/5 Criteria?
1. Interstitial pneumonitis (not pleurisy),
interstitial nephritis (not glomerulonephritis)
2. Higher frequency of lymphoma
3. Genome Screens support this with
Homing receptors found in SS but not SLE
(CXCR5)
Pathogenesis
Pathogenesis-1
•
Concordance of SS among identical twins
only about 20%
• Thus, genetic sequence is not enough and
over 80% is epigenetic— environmental
factor or gene regulation.
• Distinct histone acetylation pattern
upstream of key genes.
Pathogenesis-2
•
Large sequences of untranslated mRNA.
• Novel miRNA, some with sequence similar
to EBV fragments.
• Genetics in GWAS recently published and
only SS (not SLE) has homing receptor
(CXCR5) as a strong “hit.”
To briefly summarize
PATHOGENESIS …
Acquired Immune System-•HLA DR and Associated T-cell directed Bcell antibodies;
•IFN-g and IL-17 pathways
Innate immune system—
• Type I IFN signature
•NK like cells link acquired and innate
Clinical features and
treatment
Typical features of dry
eyes, dry mouth and swollen glands
Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s syndrome
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
Approach to treatment of benign
symptoms
a. dry eyes
b. dry mouth
c. fibromyalgia like symptoms
Normally the upper eyelid
glides over the globe on a coating called the tear film
composed
of water, protein, mucins
eyelid
orbit
Tear film
Treatment-1
Dry eyes
1. For dry eyes, must treat blepharitis before
the artificial tears will help.
2. When use ocular lubricant, be sure to use
lid scrubs in the morning.
3. Dryeyezone.com for Tranquil Eyes®,
wrap-around sunglasses with moisture
shields.
Treatment-2
Dry Eyes
4. Do not use preserved artificial tears more
than 4x per day.
5. Diurnal rhythm in practice— no Benadryl
at night.
6. Particular attention to low-humidity
environments of Operating Room and
post-op Recovery Room; O2 administration.
Caution in Sjogren’s Eye
• A sudden onset of pain and photophobia in
only one eye may be a corneal erosion
• Or it may be herpetic keratitis
• So beware of the weekend phone call
Severe Xerostomia with dry tongue
Angular
cheilitis
Treatment of Dry and
Painful Mouth
1.
2.
3.
4.
Toothpastes (avoid sodium lauryl sulfate)
Sugarless mints (Xylimelts®)
Mouth Rinses (ACT®)
Oral sprays (Oasis®)
Many products on Amazon
we urge patients
to use SS groups to buy in bulk
Sjogren’s Syndrome- Cervical Dental Caries
Treatment-2
Dry Mouth Considerations
1.
2.
3.
4.
Must treat oral candida before secretagogues.
Oral yeast can lurk under dentures.
Look for angular cheilitis.
Treatment may take a month to work.*
* This is the type of information for your web page
Treatment-3
Dry and Painful Mouth
1. Cevimeline and pilocarpine—approved by FDA–
(only meds actually approved for Sjogren’s)
2. Topical fluoride (help calcification)
by dentist at time of frequent cleaning.
Treatment-4
Dry and Painful Mouth
3. MI Paste
• Is not a toothpaste; it is a topical tooth cream that can be used
safely several times daily.
• Relieves tooth sensitivity.
• Does not irritate dry mouths caused by certain medications.
• Helps minimize tooth sensitivity before and after professional
cleaning.
• Helps to minimize tooth sensitivity after whitening procedures.
• Is helpful during orthodontics relative to helping control
(or reduce) dentin hypersensitivity.
Treatment-5
Dry Mouth Considerations
1. Avoid nasal breathing, especially at night.
2. Use nasal lavage to keep down allergic
and pollution that cause sinusitis.
3. Be aware of possibility of formation of
oral candida after treating for URTI or UTI
Take Home Lesson
Dry and Painful Mouth-1
• If you thought that Dentists did not care about SS,
then wait until you see their Dental Care Plans -The answer to all problems is a $25,000 tooth
implant.
Take Home Point
Dry and Painful Mouth-2
•
Must treat underlying oral candida (which is
erythematous spots on roof of mouth) before
anything will work.
[Candida often lurks under dentures.]
• Patients would rather run naked through clinic
than remove a denture.
Systemic Manifestations and
Treatment Considerations
1. Treatment with DMARDs largely the same as SLE.
2. In our experience, Sjogren’s patients do not tolerate
Imuran well.
3. MTX used most often to taper steroids.
4. Watch for occult biliary cirrhosis (PBC)
or non-alcoholic stator-hepatitis (NASH).
Rash distinct from SLE
(erythema annulare)
Hyperglobulemic Purpura
Most Common
Skin Manifestations
and Treatment in our Clinic
1. Xerosis--Dry skin that requires lubrication
2. We like Anthelosis topical (La Roche
Posey available on Amazon),
Lachydrin 12, and Eucerin creams
3. Look for livedo reticular, overlap
syndromes and Anti-Cardiolipin
Arthritis distinct from RA
(Jaccoud’s like)
Arthritis and Sjogren’s
• May be sero (RF) positive or sero-negative
• If anti-CCP (+), then consider RA or
psoriatic overlap
• Early onset erosive osteoarthritis
• Lupus like deformity (Jaccoud’s) in absence
of erosion
• Gout and sepsis still need to be considered
in the monoarticular flare
The most difficult aspects of
diagnosis and treatment
of systemic manifestations
in Sjogren’ syndrome:
a) lymphoproliferative
b) neurologic manifestations
High Risk of Lymphoma
Neurologic Manifestations-1
1. Symmetric peripheral neuropathies most
common-unmyelinated small fiber
(duloxetene-pregabalin if fail neurontin)
2. Demyelinating (transverse myelitis) and
optic neuritis (Devic's) (NMO)
(steroids and immune suppressants)
Neurologic Manifestations-2
4. Vasculitic –peripheral (mononeuritis
multiplex) with steroids, DMARD’s
5. Gangliopathies and plexopathies- may be
sensory, motor, autonomic or sudomotor
manifestations (steroids, IV-Ig)
6. Thrombotic—cardiolipin (steroids, anticoagulation) and perhaps rituximab
Overview of treatment of systemic
manifestations
• Steroids work
• The art of rheumatology is how to taper the
steroids
Treatment with DMARDs
• Hydroxychloroquine—remarkably little
data but placebos work
• Methotrexate and azathioprine—
generally lower than RA due to low WBC,
mouth ulcers
• Mycophenolic Acid—less renal than
cyclosporine A
• Rapamycin—I have found this useful
Treatment In SS,
several trials of anti-TNF
• Disappointing with Etanercept, Remicade
and other anti-TNF’s.
• Among RA patients with secondary SS,
little improvement in their sicca symptoms.
Previously Studied in SS
• Anti-CD20 (rituximab) –glandular,
extraglandular and fatigue
• BAFF (Belumimab)-ACR 2012 abstracts*
• Abatacept (CD40 L)-ACR 2012
• Allogeneic mesenchymal cells- ACR 2012
abstracts and article in Blood
Rituximab
• Remains the most widely used biologic in
systemic SS manifestations although not
approved
• It is approved for mixed cryoglob, ITP, and
for vasculitis-Wegener’s and MPA
(microscopic polyangiitis)
• It is approved for “rheumatoid” whether
seropositive or seronegative.
In practice
• Rituximab failed double blind studies in
both SLE and SS—but it is not given on a
regular “basis” like in RA but on an “as
needed” basis
• Rituximab had effect on tears only in early
disease and marginal effects on fatigue
• BAFF has been disappointing and
expensive
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.
SUMMARY-1
The American European Consensus
criteria:
• Subjective symptoms of dryness
• Objective evidence of autoimmune
process such as a positive antibody
to SS-A or RF
• Positive minor salivary gland biopsy
SUMMARY-2
Differential Diagnosis
Although SLE is closely related to SS, there are
distinct clinical and genetic factors.
Think of SLE as immune complex mediated and
SS as aggressive lymphocytic infiltrates
(including high risk of lymphoma).
SUMMARY-3
Additional Differential Diagnosis include:
•
•
•
•
Hepatitis C and HIV
Sarcoidosis, IgG4-related disease
Tuberculosis, Syphilis, and Leprosy
Fibromyalgia with incidental
autoantibodies
SUMMARY-4
Formulate a plan of treatment for benign
DRY EYE symptoms—
•
•
•
•
Use of artificial tears and lubricants
Punctal occlusion
Topical cyclosporin
Treat blepharitis
SUMMARY-5
Recognize systemic (extraglandular) sites
• Rule out infections and begin treatment with
DMARDs to spare steroids.
• DMARDs similar to use in SLE.
• Hydroxychloroquine
• Methotrexate, Azathioprine, mycophenolic
acid
SUMMARY-6
DMARD Therapy
Systemic symptoms- use of DMARDs
•
•
•
•
•
SLE-like symptoms
Rashes including E. annulare and
Hyperglobulemic purpura
Lymphoma
Interstitial pneumonitis and nephritis
But we are still missing key
targets in the pathogenesis
of fatigue and the
adrenal-hypothalmic axis.
• In both SS and SLE, we can lower the cytokine
with biologics, but the patient still feels little
improvement.
• This will be the focus of future direction for
therapy.
Thank you
for your time and attention
• We must look at Sjogren’s patients as a
challenge to our understanding of the
immune interaction with the autonomic and
secretory systems.
• The holy grail for neuro-immunology in the
next decade.
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.
3. Antibodies precede disease (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
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)
SUMMARY-7
Our treatment of fatigue in SS remains unsatisfactory,
and represents a great therapeutic challenge for the
next decade.
Later, we can discuss our approach to this problem
in collaboration with Salk Institute and our research
institute.
Into the future
The immuno-theology of :
• Danger Signal Hypothesis
• The immune interaction with neural
junctions as the level of the midbrain
• fMRI
Studies in collaboration with Beutler group
and Salk Institute
Summary-1
1. Functional circuit needs to be considered
when assessing “benign” symptoms of
corneal or oral pain.
2. Symptoms of oral/ocular pain do not
correlate with markers of systemic
inflammation (ESR/CRP) because the
events are contained within the brainstem
and cortex.
Normal Tearing or Salivation
Secretion requires a functional unit
gland
water
nutrients
hormones
blood vessel
water
mucin
protein
mucosal surface
afferents
efferents
lacrimatory
or salivatory
nuclei
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)
Background-3
The Functional Circuit in SS
1. Mucosal Surface
(inflammatory cytokines
and metalloproteinase)
4. Gland
(lymphs, cytokines,
metalloproteinase)
2. Midbrain
Vth Nucleus
(lymphocytes
and glial cells)
3. Vascular
(iNOS, CAMs,
Chemokines)
These sites and their cytokines correlate
with systemic manifestations
Brain
Cortex
Nociception
(pain)
glial cells and
corticcal neurons
We must understand
these sites to treat
“benign” symptoms.
The Pain Threshold is Lowered in the Tsp (-/-) mouse.
A pain stimuli that is innocuous in Wild Type
1-3
Neuroplasticity
in Pain
does cause nociceptive
pain inProcessing
tsp (-/-) mouse model.
100
Pain Sensation
80
Hyperalgesia3
Thrombospondin (-/-)
Mouse at 24 wks.
Where a trivial stimuli
Causes pain response
60
40
Pain state
Normal
Allodynia
Wild type
20
0
innocuous
noxious
Stimulus Intensity
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.
To study the mechanism of neurogenic or
nociceptive pain we must use animal model-1
• The thrombospondin (-/-) mouse (TSP null) or
the TGF-b receptor mutation both develop SS
like disease.
• The mouse develops both oral and ocular
lesions.
• The mouse develops ANA and SS-A antibodies.
To study the mechanism of neurogenic or
nociceptive pa2n
we must use animal model-2
• Thrombospondin is a matrix protein that
plays a role in activation of latent TGF-b.
• Activated TGF-b promotes Treg and inhibits
Th-17 (IFN-g).
• Thus, TSP (null) has high levels of Th-17, IL17 and IFN-g.
Thrombospondin (-/-) mouse model of SS
4 wks.
WT
24 wks
Lacrimal gland biopsies
Tsp-/-
The mouse has ANA+, SS-A+
TSP null can not activate TGF-b
In absence TGF-b , continuous Th- 17
TGF-b and cytokine activation stimulates mTor/AKT
We are also looking at
Additional Targets of Interests
• Chemokines and their receptors (CCR) on vascular cells
and lymphocytes
• TLR receptors: SLAC-15 that links Toll receptor and type
1 IFN
• Methylation modulators and siRNA
• Neural mediator circuits:
• Receptors on cornea--substance P (TRPV1), VIP and
CGRP pain receptors
• TRPM8, TRPA1, and CGRP in trigeminal ganglion neurons
• Trigeminal ganglion neurons- MCP-1, MIP-2,
• CCR and CCL at the blood brain barrier
The tsp-null mouse allows us to look at the interaction
of peripheral inflammation and microglial cells
• Activation of microglial cells through mTor/AKT
• In absence of thrombospondin, constitutive
activation of Th17 and IFN-g activates microglial
cells
• Nociceptive (pain) pathway occurs through
smad3 and non-smad pathways that involve
mTor/AKT pathways in cranial nerve V
Model for stress induction
(attach mouse by velcro to
stuffed cat)
Moulton et*. Al used fMRI in SS patients with chronic ocular pain
using fMRI of nociceptive pain have been studied
Cortical regions that
activate with ocular pain
signal at “benign stimuli
levels” occur only in
chronic SS patients with
severe pain
*Moulton EA, Becerra L, Rosenthal P, Borsook D. An Approach to
Localizing Corneal Pain Representation in Human Primary Somatosensory
Cortex. PloS one 2012;7:e44643.
Similar pattern of
Fos-ir in PVH neurons
in response to distinct stressors
Emotional
Physiological
Thank you
for inviting me to participate
in this wonderful meeting.
We will discuss treatment of dryness of eyes
and mouth during afternoon session.
CCR and Blood Brain Barrier