SJOGREN’S SYNDROME:
Theory to Practice
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiM Medical Center
La Jolla, California USA
robertfoxmd@mac.com
Goals-1:
1) There are no FDA approved drugs for the
systemic manifestations of Sjogren’s
syndrome
2) Therefore, expert opinion must be used to
choose therapies based on literature
3) These recommendations are summarized in
my new chapter in UpToDate
Goals-2
3. The existing treatment borrows from RA
and SLE in the use of DMARDs, as well as
interstitial pneumonitis and lymphoma
4. The most widely used biologic is
rituximab, although not approved by FDA.
5. The question is when to use DMARD or
Biologic Agent
Goals-3
The most challenging issues for
therapy
6. Neurologic Manifestations—including
peripheral neuropathy, ganglionopathy, and
central nervous involvement
7. Fatigue and cognitive loss
8. Lympho-proliferative swelling and possible
lymphoma
All slides are available and can be
downloaded
from my website
using your desktop computer
robertfoxmd.com
(although these may not be
accessed by iPhone due to our web
security)
5
“Old” Consensus Criteria, 2002
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)
A new consensus criteria is being developed
with slightly different features
It will be called the SICCA-AECG criteria
ESSDAI- European SS Activity Index
(to assess if therapy working)
• 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.
• Clinical significance is 3.5 units of change
Systemic Manifestations
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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 Studied in SS
• Anti-CD20 (rituximab)* –most widely used in SS
although FDA approved
• Belimumab (BAFF)-has been disappointing in SS
• Abatacept (CD40 L)-Phase II safety good—
improved ESSDAI but no control arm
• TNF antagonists shown not useful
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.
EYE DRYNESS results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s Syndrome
Artificial tears
Punctal occlusion
Ocular lubricants
Treat blepharitis first
Topical cyclosporin
Topical “soft” steroids
often
Used if not able totolerate
Restsis alone
Systemic Ocular
Often need DMARDs
• Topical or intra-ocular steroids
• Recurrent uveitis –may get by with
azathioprine or cell cept
• Retinal vasculitis-may need rituxan or
cyclophosphamide
• Watch out for ocular herpetic lesions
Rash distinct from SLE
(erythema annulare)
the “old” subacute SLE which is negative for
complement staining
Therapy of skin lesions
• Hydroxychloroquine for E. annulare
or methotrexate if psoriaform
• Vasculitis (usually small vessel) may need methotrexate
• Vasculitis of mixed cryoglobulinemia responds to
rituximab (indication approved by FDA)
• Mono-neuritis multiplex (medium vessel) may also
require cyclophosphamide
Arthritis distinct from RA
(Jaccoud’s like or erosive OA)
Hydroxychloroquine, Methotrexate, Rituximab
(less successful with azathioprine or leflunomide limited by leukopenia)
Parotid swelling
(after rule out infection and lymphoma, steroids and rituximab)
Lymphocytic Interstitial Pneumonitis
Bi-basilar on CXR
Prominent Cystic on CAT
Lymphocytes on biopsy
Lung involvement
(after rule out TBC, MAI,
Lymphoma)
• Interstitial pneumonitis—steroid and
Mycophenolic acid; have avoided MTX
due to MTX lung
• Rituximab
DeVic’s Syndrome:
Transverse Myelitis Neuromyelitis Optica
After rule out infection, treatments with cytoxan and or rituximab.
Maintenance with azathioprine
May need to treat like multiple sclerosis—new options approved
Lymphocytic Interstitial Nephritis
(steroids, mycophenolic acid, rituximab)
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-3
Additional Differential Diagnosis include:
• Celiac disease
• Hepatitis C and HIV
• Sarcoidosis, IgG4-related disease
• Tuberculosis, Syphilis, and Leprosy
• Fibromyalgia with incidental autoantibodies
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-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
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.
Information on website
Benign manifestations include:
•
•
•
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Dry and painful eyes
Dry and painful mouth
Myalgias, arthralgia, fatigue
Impaired cognition (executive
function)— trying to distinguish
“fibromyalgia” from “depression”
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)
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
RobertFoxMD@mac.com