sjogren’s syndrome: theory to practice in san diego robert i. fox, m.d., ph.d. carla m. fox, rn...
TRANSCRIPT
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
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
• 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 approachI 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 CXRProminent Cystic on CATLymphocytes 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.
Additional Differential Diagnosis includes:
• Celiac disease
•Hepatitis C and HIV
•Sarcoidosis, IgG4-related disease
•Tuberculosis, Syphilis, and Leprosy
•Fibromyalgia with incidental autoantibodies
SUMMARY - 2
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
• 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 LossAlso found in multiple sclerosis
The elephant in the Room
FatigueCognitive
Nervepain
Dry eyes and dry mouth
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.
0
Neuroplasticity in Pain Processing1-3
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.
Stimulus Intensity
100
Pain state Normal
Allodynia
Hyperalgesia3
80
60
40
20
innocuous noxious
Pai
n S
ensa
tio
n
Moulton et*. Al used fMRI in SS patients with chronic ocular painusing 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
EmotionalEmotional PhysiologicalPhysiological
Similar pattern of Fos-ir in cortical neurons in response to distinct stressors
Thrombospondin (-/-) mouse model of SS
4 wks.
Lacrimal gland biopsies
The mouse has ANA+, SS-A+TSP null can not activate TGF-In absence TGF-continuous Th-17TGF- and cytokine activation stimulates mTor/AKT
WT Tsp-/-
24 wks
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-activates microglial cells.
At the level of the Vth nerve(Tsp -/- mouse)
• Microglial cells translate inflammatory signals that go to nociceptive cortex
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.