Download - Dr. Robert Fox

SJOGREN’S SYNDROME:
Theory to Practice
in San Diego
Robert I. Fox, M.D., Ph.D.
Carla M. Fox, RN
Scripps Memorial Hospital
Scripps/XiMED Medical Center
La Jolla, California USA
[email protected]
Take home lesson 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 chapters with Alan Baer in UpToDate
Take home lesson-2
1. Steroids work
2. Long term steroids have complications
3. The definition of a rheumatologist is how to
get a patient off steroids
Take home lesson-3
• DMARDs -MTX, LEF, AZA similar to RA
or SLE
• Immune suppressants-Mycophenolic acid ,
cyclosporin A, and Rapamycin
Old drugs in new ways
• Cytotoxics-cyclophosphamide with new
lower dose regimens
• Anticoagulants and treat co-morbid
conditions such as cardiovascular or
thrombosis
The most challenging issues
for SS therapy-1
1. Neurologic Manifestations—including
peripheral neuropathy, ganglionopathy,
and central nervous involvement.
2. Lymphadenopathy and lymphoma
The most challenging issues
for SS therapy-2
3. IgG4 Related Disease Spectrum
4. Infections mimicking or occurring in SS
Fatigue and cognitive loss-3
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•
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Recognize depression
Recognize sleep disorders
Recognize autonomic neuropathy (POTS)
Remember large number of patients needed
to show efficacy of anti-depressants
statistically due to placebo effect
Fatigue and cognitive loss-4
• Our therapies are poor
• Need for new disease models and better
therapy
• Recognize placebo effect in anecdotal
report
Our future approach
I have left to discussion period our
collaborations with:
• Ramachandran (Salk) regarding phantom
pain and neurochemistry of "veto" neurons
• Beutler (Scripps) and innate immune
mechanisms of fatigue (post viral model)
• Oldstone (Scripps) for fatigue of multiple
sclerosis and mouse viral model (LDL and
cyclo-oxygenases)(Receptys)
Current critical issue in the patient
with intractable eye symptoms
The dissociation between ocular symptoms and objective findings:
The patient with severe discomfort or complaints-but relatively mild objective ocular surface
a) meibomian gland dysfunction (blepharitis)
b) irritant or allergic effects to preserved tears or ocular meds
New Concept in patient where ocular
symptoms are out of proportion to
symptoms
(pioneered by Rosenthal et al at Harvard
Cornea Unit in the post-Lasik patient)
Central pain syndrome: "phantom pain"
a loss of corneal nerve density
and up-regulation of central pain processing
(conforcal microscopy of cornea
and fMRI of brain)
Systemic
Extraglandular Manifestations
• Steroids work… but-– The definition of a rheumatologist is how to
taper steroids.
• Anti-malarials (HCQ, Quinacrine)
• DMARDs-MTX, Leflunomide,
Mycophenolic Acid
• Biologics
Hydroxychloroquine
• Current debate about "efficacy" --we use it
when we are dealing with increased ESR,
rash, or arthritis. Current debate is about
"fatigue" only.
• Efficacy in SLE was convincingly shown in
"withdrawal studies," and those need to be
done in SS patients.
• Issue of cost/benefit of OCR monitor and
total dose vs. daily dose based on weight.
Biologics studied in SS
(that show some promise)
• Anti-CD20 (rituximab)* –most widely used in SS
and Europe for SS although FDA approved.
• Belimumab (BAFF)- has been disappointing in SS
in terms of patient's self assessment.
• Abatacept (CD40 L)-Phase II safety good—
improved ESSDAI, but no control arm.
Rituximab*
• Most widely used biologic in SS (ACR 2013
abstracts) in French and Scandanavian registries.
• Used in response to extraglandular manifestations
such as persistent glandular swelling, pneumonitis,
mixed cryoglobulinemia.
• New "black box" to rule out hepatitis B.
• *Not approved by FDA.
Other challenging problems
• Lymphoma-- MALT or diffuse lymphoma,
or just an atypical lymphoid reaction.
• Interstitial pneumonitis and nephritis-huge issues in sample variation during
biopsy.
Persistent parotid gland swelling
(after rule out of infection and lymphoma, steroids and rituximab)
Lymphocytic Interstitial Pneumonitis (LIP)
Bi-basilar on CXR
Prominent Cystic on CAT
Lymphocytes on biopsy
SUMMARY - 1
1. Symptoms of ocular and oral symptoms
are often greatly out of proportion to
objective findings.
2. This may be due to augmentation of
"central pain" pathways.
SUMMARY - 2
Additional Differential Diagnosis includes:
• Celiac disease
• Hepatitis C and HIV
• Sarcoidosis, IgG4-related disease
• Tuberculosis, Syphilis, and Leprosy
• Fibromyalgia with incidental autoantibodies
SUMMARY - 3
• Our treatment of fatigue in SS remains
unsatisfactory, and represents a great
therapeutic challenge for the next decade.
• The pathways may be similar to PTSD, and
animal models indicate new pathways such
as prostaglandins-- the mouse viral model.
Thank you for your time
and attention
Acknowledgement-Scripps
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Bruce Beutler and Ari Theofilopoulos
Role of innate system in fatigue
Mike Oldstone and Frank Chishari
Mechanism of fatigue in MS and role of
cyclooxygenases and sphingosines
Acknowledgments Salk
• V. Ramachandran and Sarah Stone
• Role of phantom pain and veto neurons
• Role of Vth cranial nerves neurokines
Cognitive: Executive Function Loss
Also found in multiple sclerosis
The elephant in the Room
Fatigue
Cognitive
Dry eyes and
dry mouth
Nerve
pain
The concept of pain plasticity is
well known to psychologists
(we collaborate with
V. Ramachandran at Salk Institute)
The concept of “phantom pain”
will be important later as we deal
with "brain fog" or "neuropathy."
To estimate the role of "central pain,”
we use the method of Rosenthal et al
at Harvard Cornea Clinic
for patients with severe pain after Lasik cornea surgery
1. We score the pain level (1-10) and then use
ophthaine to anesthetize the eye-- then rescore the pain.
2. Early in disease, the ophthaine completely reverses
pain, but later in course, a much lower decrease.
Neuroplasticity in Pain Processing1-3
100
Hyperalgesia3
Pain Sensation
80
60
40
Pain state
Allodynia
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.
3. Cervero F, Laird JMA. Pain. 1996;68:13-23.
Normal
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.
Emotional stressors potential the role of cytokines
in pain pathways
Emotional
Physiological
Similar pattern of Fos-ir in cortical neurons in response to distinct stressors
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
The tsp-null mouse allows us to look
at the interaction of peripheral inflammation
and microglial cells-1
• Activation of microglial cells through
mTor/AKT.
• In absence of thrombospondin,
constitutive activation of Th17 and IFN-g
activates microglial cells.
• Microglial cells translate inflammatory
signals that go to nociceptive cortex
At the level of the Vth nerve
(Tsp -/- mouse)
WT
TSP (-/-)
mTor and AKT activated in
response to “lower stimuli”
in the tsp (-/-) mouse
Don’t miss other causes of ocular
pain
• Topical or intra-ocular steroids in uveitis.
• Recurrent uveitis–- may need azathioprine
or mycophenolic acid.
• Retinal vasculitis-- may need rituximab or
cyclophosphamide.
• Watch out for ocular herpetic lesions.
• Make sure not a fungal or embolic lesion.
Other sites of systemic involvement
Lymphocytic Interstitial Nephritis
(steroids, mycophenolic acid, rituximab)
Lung involvement
• Rule out TBC, infections including MAI, and
lymphoma.
• Interstitial pneumonitis–
Steroid and Mycophenolic acid;
-- Have avoided MTX due to MTX lung
• Rituximab useful, but rarely will exacerbate
Lung and Renal Involvement:
(basis for treatment)
• We like initial steroids and tapered steroids
with mycophenolic acid or perhaps rituximab.
• We saw many UIP/DIP and interstitial nephritis
biopsy samples at Stanford (Carrington and
Dorfman in our Pathology Department)
• At the same time, mycophenolate was
developed there for our transplant program.
Lymphoma or Pseudolymphoma
• Stanford was a lymphoma center.
• We also developed rituximab at Stanford
(Levy lab). and it had low toxicity
• A lot of Levy post docs founded IDEC across
street from Scripps.
• One of first uses of Rituxan was a member of
the Scripps family.
• Ask me how we arrived at 375mg/m2 dosing.