Transcript Treatment Strategies in the management of Sjogren`s Syndrome

SJOGREN’S SYNDROME:
Theory to Practice
in San Diego
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiM Medical Center
La Jolla, California USA
[email protected]
Thank you for inviting us to your
beautiful city
• Tack för inbjudan
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
Therapy of SS
1. The treatment for SS uses steroids and
NSAIDS in same manner as SLE and RA
2. Lymphoproliferation and demyelininating
disorders distinguish therapy
3. The role of rheumatologist in SS is how to
taper steroids
Take home lesson-3
• 3. Immunosuppressants including
mycophenolic acid, cyclosporin A and
rapamycin are useful and not fully utilized
• 4. Attention to co-morbid conditions such as
anti-coagulants and accelerated
atherosclerosis
Take home lesson-3
• Coordinate therapy for dry eyes and dry
mouth
• Determine if patient is using medications
with anti-cholinergic side effects
• Evaluate the causes of fatigue--depression,
sleep disorders, or whether we just do not
understand the process
Take home lesson-3
The most challenging issues for SS therapy
1. Neurologic Manifestations—including
peripheral neuropathy, ganglionopathy, and
central nervous involvement
2. Fatigue and cognitive loss
3. Lympho-proliferative swelling and possible
lymphoma
Current 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 and irritant or allergic effects
(tear breakup and osmolality)
b) Central pain syndrome: a loss of corneal nerve density
and up-regulation of central pain processing
(conforcal microscopy and fMRI)
To estimate the role of "central pain", we use the
method of Rosenthal et al at Harvard Cornea Clinic
1. We score the pain level (1-10) and then use opthaine
to anesthesitize the eye--then rescore the pain
2. Early in disease, the ophthaine completely reverses
pain but later in course a much lower decrease
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"
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
• 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
Systemic Extraglandular
Manifestations
• Steroids work
• The definition of a rheumatologist is how to
taper steroids
• Anti-malarials
• 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
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
• 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 swelling
(after rule out infection and lymphoma, steroids and rituximab)
Lymphocytic Interstitial Pneumonitis (LIP)
Bi-basilar on CXR
Prominent Cystic on CAT
Lymphocytes on biopsy
Thank you for your time and
attention
• We can stop for questions or
• We can tell some of the history of how we
came to use rituximab and mycophenolic
acid--the actual history had less to do with
science than luck
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 Path Dep't)
• 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?
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-3
Additional Differential Diagnosis include:
• Celiac disease
• Hepatitis C and HIV
• Sarcoidosis, IgG4-related disease
• Tuberculosis, Syphilis, and Leprosy
• Fibromyalgia with incidental autoantibodies
SUMMARY-4
• 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
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)
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