Download - Dr. Robert Fox

SJOGREN’S SYNDROME:
Diagnosis and Therapy
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiM Medical Center
La Jolla, California USA
[email protected]
Learning Objectives:
By the end of the session,
the participant will be able to:
1) Define
European should
criteriabe
forable to:
thethe
participants
diagnosis of Sjogren’s Syndrome (SS)
Symptoms of dry eyes and mouth
Objective evidence of autoimmunity:
(either a SS-A/SS-B or a positive lip biopsy)
Learning Objectives
3) List 2 glandular manifestations of SS.
Dryness of eyes or mouth
Lymphoproliferation or lymphoma of lacrimal or
salivary glands
involvement with SS presentations.
Learning Objectives
Describe at least 4 sites of extraglandular
involvement in Sjogren’s syndrome
Skin-vasculitis
Lungs-interstitial pneumonitis or BALT
Kidneys-interstitial nephritis
Neurologic-peripheral or central
Learning Objectives
Identify at least 3 differential diagnoses
that are difficult to distinguish from Sjogren’s
Syndrome.
SLE—altho they often co-exist, there are differences
IgG4-related disease. This is a newly defined
comples of diseases
Idiopathic Neurologic disorders with an incidental
SS-A
All slides are available
on my website
robertfoxmd.com
6
Background-1
SS has “benign” and “systemic”
manifestations.
Background-2
Benign manifestations include:
•
•
•
•
Dry and painful eyes
Dry and painful mouth
Myalgias, fatigue
Impaired cognition (executive
function)— trying to distinguish
“fibromyalgia” from “depression”
SS Related Health Care Costs1:
•
Dry or painful eyes are now most
common cause of visits to
Ophthalmologists in U.S. and Japan.
• Lost productivity (over $160 billion/year just
for dry eyes (especially in computer users
where decreased blink rate is 90%.
Sjogren’s symptoms
are so debilitating,
that patients would:
• equate SS with impact similar to
moderate angina.
• trade 2 years of “life expectancy”
to not have SS symptoms.
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
SS-Related Health Care Costs-3:
Despite these costs of health care,
patient and physician dissatisfaction
with clinical outcomes
is higher in pSS
than in SLE or RA.
Diagnosis
of
Sjogren’s Syndrome
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)
Most important “child” of AECC was the ESSDAI
(European Sjogren’s Syndrome Activity Index)
which includes 16 domains of activity score
including glandular and extraglandular activity
• The ESSDAI ranges from 1-130
• Practically, the range is 1-41
• A clinically meaningful change is 3.5 units
•
•
•
•
Constitutional
Skin
Lung, Renal
Neurologic
ESSDAI- European SS Activity Index
• Weighted domains to give a total score—
the Sjogren’s equivalent to ACR-50 for RA.
• The validated ESSDAI activity score has
been the accepted outcome measure of
FDA clinical trials.
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.
• The SICCA criteria will need to be modified,
and committees are now at work to form a
new consensus criteria.
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.
Clinical Manifestations
• Benign --
glandular dryness
• Systemic -- extraglandular
Clinical Key Points : Dry Mouth
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
Rash distinct from SLE
(erythema annulare)
Arthritis distinct from RA
High Risk of Lymphoma
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
Leprosy
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.
Is Sjogren’s just SLE
with 4/5 SLE Criteria?
• Different antibody profile (antiSSA/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)
Lymphoma and Type II mixed
cryoglobulinemia
Lymphocytic Interstitial Pneumonitis
Bi-basilar on CXR
Prominent Cystic on CAT
Lymphocytes on biopsy
DeVic’s Syndrome:
Transverse Myelitis Neuromyelitis Optica
Lymphocytic Interstitial Nephritis
Pathogenesis-1
• Genetics
• Environmental Factors
• Cytokines of innate and acquired immune
system
Pathogenesis-2
•
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-3
•
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.”
Pathogenesis-4
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
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)
Pathogenesis-5
Genome-Wide Association Parallels-our studies on cytokine profiles
• Strongest is HLA-DR and acquired immune system leading
to T-cell/B-cell production of autoantibody.
• Next strongest are Innate Immune markers associated
with Type 1 IFN production.
• As noted above, also find a homing receptor (CXCR5)
which goes with the tissue-specific homing receptors.
• In SS patients with lymphoma, find A20 (member of
TNF superfamily) that suppresses NFK-b and B-cell
proliferation.
Treatment of DRY EYE
Benign Symptoms-1
•
•
•
•
•
Artificial tears and lubricants
Punctal occlusion
Do not use preserved tears more than 4x/day
Topical cyclosporin (Restasis)
Recognize and treat blepharitis
DRY EYE Therapy-2
• Special needs in operating room (low
humidity and high risk corneal abrasion)
• Avoid Lasik eye surgery
• Look for “lid lag” and exposure zone
keratopathy.
Treatment of DRY MOUTH-1
•
•
•
•
Artificial Saliva, mouth rinses and sprays
Secretagogues-pilocarpine and cevimeline
Fluoride to prevent caries
Treat oral candida (often under dentures)
Treatment of DRY MOUTH-2
• Avoid medications with anti-cholinergic
side effects (esp. over the counter
medications at night) such as Benadryl or
amitryptilline.
• Keep nasal passages open to avoid mouth
breathing.
• Recognize gastric reflux at night (laryngotracheal reflux)
Patient Education
• Time does not permit patient education at
time of office visit.
• Create and use an internet site for common
questions about treatment.
• Feel free to use information from my
website for your patients.
Systemic Manifestations
•
•
•
•
•
•
Steroids work but have side effects.
DMARDs to taper or replace steroids.
Hydroxychloroquine
Methotrexate, Azathioprine
Mycophenolic acid mofetil
We are interested in Sirolimus (rapamycin)
Biologics Previously Studied
in SS
• Anti-CD20 (rituximab)* –glandular swelling,
extraglandular renal and lung, mixed
cryoglobulinemia
• BAFF (Blys)-ACR 2012 abstracts has been
disappointing
• Abatacept (CD40 L)-ACR 2012
Rituximab
• Most widely used biologic in SS (ACR
2013 abstracts).
• Used in response to extraglandular
manifestations such as persistent glandular
swelling, pneumonitis, mixed
cryoglobulinemia.
• Not approved by FDA.
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.
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
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.
Thank you
for your time and attention
• ‫شكرا لك على لطفك واالهتمام‬
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.
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.
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.
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.
Dry and Painful Mouth-3
• Angular cheilitis the most obvious hint.
• Treatment of oral candida is a slow process
involving multiple steps.
• Use website for education.
We are also looking at
additional targets of interest
• 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
CCR and 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
Thank you for inviting us.
Robert I. Fox, M.D., Ph.D.
http://www.robertfoxmd.com
[email protected]