Download - Dr. Robert Fox

Sjogren’s Syndrome:
Evolving Concepts of Treatment
based on Pathogenesis
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
and Research Institute
La Jolla, California USA
[email protected]
Acknowledgements
Carla Fox, R.N.
Clinical Coordinator and Medical Editor
Scripps Memorial Hospital
and Research Foundation
Karin Tatsumoto, M.D.
Daiichi Sankyo
Tokyo, Japan
Disclosure
I have worked as Principal Investigator in
multicenter trials for:
a)
b)
c)
d)
e)
MGI (Pilocarpine)
Daiichi (Cevimeline)
Genentech and Amgen
(Etanercept and rituximab)
Aventis (leflunomide)
Allergan (Restasis)
Goals - 1
a) Recognize the Symptoms and Signs of
Sjogren’s Syndrome.
b) Understand the principles of treatment of
dry eyes and dry mouth.
Goals - 2
Looking into the future:
c) Why is a “neurotransmitter” (cevimeline) useful
in an autoimmune disease?
d)
How does an “autoimmune” disease like SS
provide insight into:
•
•
•
Multiple Sclerosis
Alzheimer’s disease
Fibromyalgia
where dryness is present due to
cholinergic outflow imbalance?
Take Home Lesson - 1
1. Sjogren’s is characterized by dry eyes and dry
mouth due to lymphocytic infiltrates in the
glands.
2. The glands are not “totally destroyed” (only
50% of the acini and ducts are damaged).
3. The the residual glands are “paralyzed” by local
release of cytokines and metalloproteinases.
Take Home Lesson - 2
3. Therapy of Sjogren’s requires attention to
topical treatment of dry mucosal surfaces
and systemic therapy for extraglandular
manifestations.
4. Sjogren’s provides a prototype to
understand the interaction of immune
effects on exocrine, endocrine, and
neurocrine function.
Background
Historical
1892 - Mickulicz describes KCS (but term too
vague-did not distinguish TBC and lymphoma)
1933 - Sjogren (distinguished from Vitamin D deficiency)
1953 - Morgan and Castleman- NEJM CPC
1956 - Bloch, Buchanan, Wohl, Bunim- Medicine
defined the disease as we know it today
1980’s - Criteria consensus established for Sjogren’s
1990 - Organized therapeutic trials based on
rational understanding of pathogenesis
New International Criteria - 1
1. Ocular Symptoms
2. Oral Symptoms
3. Salivary gland function
(flow rate by flow rate, scan, or sialography)
AND
4. Histopathology (focus score > 1)
5. Autoantibody to SS-A or SS-B
New International Criteria - 2
New Criteria for SS (cont’d)
Exclusions:
•
Pre-existing lymphoma, sarcoid
•
Hepatitis B or C (15% in EEC)
•
Drugs with Anticholinergic side
effects
(measurements of tear/saliva with
patient off drug for 3 half lives)
What is Sjogren’s?
There is good agreement about diagnosis
for the patient with florid symptoms
of keratoconjunctivitis sicca (KCS),
parotid swelling,
and
high titer ANA with SS-A/SS-B.
Issues in the patient
with true Sjogren’s
1. Treatment of Dry Eyes and Mouth
2. Extent and treatment
3. Reassurance
of
And
extra glandular Disease
Education
• steroids
encourage patients to access
• DMARDs
internet via Google Scholar
• biologics
(rather than Google)
Fibromyalgia /Cognitive
Symptoms
Two of the most difficult diagnostic and
therapeutic situations:
•
•
The patient with documented SS,
who has symptoms of fibromyalgia and cognitive loss;
AND:
The patient with complaint of
dryness and a positive ANA
but with little else to suggest an autoimmune process.
Are the symptoms related to SS?
Differential Diagnosis in
Fatigue and Cognitive Loss
1. Primary Sjogren’s with secondary fibromyalgia
3. Other causes:
• Demyelination
• Neuropathy
• Atherosclerotic/thrombotic
infection
2. Patient with
complaints of
• Dryness and Fibromyalgia
but little else to suggest SS
Fibromyalgia
Fatigue and cognitive change are major
causes of disability in Sjogren’s syndrome.
These complaints are so dominant
that they often make clinical trials in SS
or SLE difficult to interpret.
Clinical Clues to Diagnosis of
Cognitive Loss and Fatigue
Primary Sjogren’s
• CNS vasculitis - ESR, CRP, spinal fluid
• Thrombosis -- anticoagulants
• Infection - CRP, spinal fluid
• Demyelinating lesion - MRI, spinal fluid
• Accelerated atherosclerosis - lipid profile, homocysteine
• Hypothyroid
• Autonomic Neuropathy
• Drug toxicity
• Sleep disorder
(apnea, nocturnal myoclonus)
•Fibromyalgia
•Obsessive/Compulsive Disorder
•Attention Deficit Disorder
•Depression
We have found brief
neuro-psychometric testing
helpful to guide therapy:
1. Assess for (true) disability- medical/legal,
especially if they are seeking disability benefits
(although rare to find organic brain syndrome, the results are
used to help patients alter their lifestyle)
2. Assess for depression- (duloxetene/milnicaprin or
pregabalin approved therapy for fibromyalgia in US).
Tricycyclics unlikely to be tolerated due to dryness
3. Assess decreased “executive function”
(i.e., multi-tasking) often exacerbated by stress
< modafalin-Provigil >
Pathogenesis
Pathogenesis of Sjogren’s:
the major misunderstanding
The salivary and lacrimal glands are not fully destroyed.
In fact, only 50% of the acini and ducts are destroyed.
The residual ducts are not functioning due to
the release of cytokines and metalloproteinases.
In Sjogren’s syndrome,
many acini and ducts are spared
Areas of “lazy” gland
Sjogren’s
Lymphocytic
infiltrate
Normal
The key question is:
Why do the residual acini/ducts
not function optimally?
The glands and neural innervation
are present.
and…
How does this relate to
symptoms, pathogenesis and therapy?
When patients describe
irritation of eyes or mouth…
they are describing
increased friction
as the lid transverses the globe,
or the tongue moves over
the buccal mucosa.
Normally the upper eyelid
glides over the globe
on a coating called the tear film
composed of water, protein, mucins
eyelid
orbit
tear film
When the tear film is inadequate,
the upper lid sticks to the surface of the orbit
and actually pulls off the surface layer
of the ocular surface.
eyelid
orbit
Tear film
The
Sjogren’s
patient is
describing
increased
friction
as the upper
lid moves
over the globe
Dryness results in the clinical appearance of
keratoconjunctivitis sicca (KCS)
characteristic of Sjogren’s syndrome
The upper lid
literally sticks to
the surface epithelial
surface and pulls
surface mucin layers off.
The Rose Bengal
dye retention
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.
Sjogren’s and Dry mouth
The decrease in saliva leads to:
• Difficulty swallowing and talking
• Increased incidence of dental decay
Sjogren’s Syndrome- Cervical Dental Caries
To understand the symptoms of
SS and the role of cevimeline…
We must first review the concept of
the functional circuit
that governs tear and saliva.
Normal tearing or salivation
secretion requires a functional unit
4. gland
water
nutrients
hormones
3. blood vessel
water
mucin
protein
1. mucosal surface
afferents
efferents
2. lacrimatory
or salivatory
nuclei in
midbrain
cortical
input
Central Nervous
System
Sjogren’s syndrome
affects functional unit
1. ocular surface
(cytokines, MMP, growth factor)
4. Gland
cytokines,
Autoantibodies
metalloproteinases
Cholinergic
efferents
lymphocytes
3. blood vessel
Chemokines
CAMs
iNOS
adrenergic
2. Central Nervous
System
(HPA axis)
Reasons for glandular dysfunction
in Sjogren’s
1. Cytokines (especially IL-1, TNF)
interfere with release of Ach/VIP
from nerve endings
and
2. Response to Ach by glandular cells
Metalloproteinases interfere with
Gland-extracellular matrix
Acetyl Choline Receptors
of Muscarinic Type 1 and 3
are found on salivary and lacrimal glands
3. M1 receptor (neuroprotective)
gland
1.
acetyl choline
M3 receptor
(regulates water channel)
M3 receptor
2. Acetylcholine released
from nerve synapse
stimulates
M1 and M3 receptors
nerve
Muscarinic Receptor
Actions
a)
M1 receptor: neuroprotective and
anti-apoptotic properties for neurons
b)
M2 receptor: (found on cardiac tissues)
c) M3 receptor: secretory function of gland
Cevimeline (Evoxac)
1. A sterically constrained form of Ach
2.
Known in neurochemistry literature as
AF102b and SN-2011
3.
Selected for its M1 and M3 activity in:
•
•
•
Neuroprotection assay
Alzheimer’s model of rat maze learning
Benefit in stimulating saliva and tears
Early in the clinical trials of
cevimeline in Alzheimer’s
Increased salivation
was noted as a side effect,
leading to its trials
in Sjogren’s syndrome.
Examples of Cevimeline
Efficacy in SS by
Rheumatologists, Ophthalmologists, Dentists
1. Yamada H, Nakagawa Y, Wakamatsu E, et al. Efficacy prediction of cevimeline in
patients with Sjogren’s syndrome. Clinical Rheumatology. 2007;26(8):1320-1327.
2. Mavragani CP, Moutsopoulos HM. Conventional Therapy of Sjogren's Syndrome. Clin
Rev Allergy Immunol. Jun 2007;32(3):284-291.
3. Samarkos M, Moutsopoulos HM. Recent Advances in the Management of Ocular
Complications of Sjogren's Syndrome. Curr Allergy Asthma Rep. Jul 2005;5(4):327-332.
4. Petrone D, Condemi JJ, Fife R, Gluck O, Cohen S, Dalgin P. A double-blind, randomized,
placebo-controlled study of cevimeline in Sjogren's syndrome patients with xerostomia
and keratoconjunctivitis sicca. Arthritis Rheum. Mar 2002;46(3):748-754.
5. Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treatment of xerostomia in
patients with Sjogren syndrome: a randomized trial. Arch Intern Med. Jun 10
2002;162(11):1293-1300.
6. Fox RI, Konttinen Y, Fisher A. Use of muscarinic agonists in the treatment of Sjogren's
syndrome. Clin Immunol. Dec 2001;101(3):249-263.
7. al-Hashimi I. The management of Sjogren's syndrome in dental practice. J Am Dent
Assoc. Oct 2001;132(10):1409-1417; quiz 1460-1401.
8. Fox RI, Stern M, Michelson P. Update in Sjogren syndrome. Curr Opin Rheumatol.
2000;12(5):391-398.
Leung, A. S. McMillan, M. C. M. Wong,
W. K. Leung, M. Y. Mok and C. S. Lau
Clinical Rheumatology 27: 429 (2008)
“The efficacy of cevimeline hydrochloride in the
treatment of xerostomia in Sjogren’s syndrome in
southern Chinese patients: a randomized double blind,
placebo-controlled crossover study”
Among 52 patients, significant improvement after
treatment with cevimeline:
a) Xerostomia Inventory (XI),
b) the General Oral Health Assessment Index (GOHAI),
c) Trend toward improve the Ocular Surface Disease Index (OSDI)
and the Medical Outcomes Short Form (SF-36).
Use of Pilocarpine in Taiwan
for dryness-including Sjogren’s, radiation and drug side effects
1. Wu CH, Hsieh SC, Lee KL, Li KJ, Lu MC, Yu CL. Pilocarpine
Hydrochloride for the Treatment of Xerostomia in Patients with Sj
ren's Syndrome in Taiwan-A Double-blind, Placebo-controlled Trial.
Journal of the Formosan Medical Association. 2006;105(10):796803.
2. Liu X, Zeng Z, Hong M, Zhang A, Cui N, Chen F. Clinical Analysis
of Xerostomia in Patients with Nasopharyngeal Carcinoma after
Radiation Therapy. The Chinese-German Journal of Clinical
Oncology. 2005;4(3):137-140.
3. Chien YW, Lin S. Optimisation of Treatment by Applying
Programmable Rate-Controlled Drug Delivery Technology. Clinical
Pharmacokinetics. 2002;41(15):1267.
4. Zucheng W, Xiaoling S, Heding X. A Controlled Clinical Study of
Pilocarpine Nitrate in the Treatment of Dry Mouth Caused by
Psychotropic Drugs. CHINESE JOURNAL OF PHARMACO
EPIDEMIOLOGY. 2000;9(2):59-60.
Cevimeline is a neurotransmitter that mimics acetylcholine.
and binds to Receptors of Muscarinic Type 1 and 3
gland
M1
M1 receptor mediates
glandular resistance to “shock”
and facilitate regrowth
M1 M1
cevimeline
nerve
Cevimeline actions
1. Stimulates water transport (M3 receptor)
2 Protects the gland from stress (M1 receptor)
3. Up regulates new proteins (defensins/histatins)
4. Alters post translational modification of salivary proteins
5. Stabilizes aquaporin 3 and 5 -(both receptors are important in brain and gland)
Drugs such as Aricept or Excelon
currently approved for Alzheimer’s
work to improve memory
by inhibiting acetylcholine esterase
and thus, increasing Ach in the gap
Acetyl cholinesterase
ACh
Cevimeline actions
•
In Alzheimer’s studies, it remains the only drug ever
shown to decrease the level of beta amyloid plaque in
CNS of Alzheimer’s patients.
•
However, sweating and salivation as side effects
limited cevimeline clinical use in Alzheimer’s,
and led to development of Aricept.
Pilocarpine (Salagen)
1.
Derived from shrub jaccorhandi pilocarpi.
2.
Used by natives in South America
(known as slobber mouth).
3.
Introduced into Europe in late 1860’s
based on its ability to induce profound sweating.
4.
In 1893, used for a patient with xerostomia.
5.
In 1990’s, used for radiation xerostomia and later
for Sjogren’s syndrome.
Muscarinic Receptors
There are at least 5 receptors (M1-M5),
but we will concentrate on M1 and M3 mAChR
that are found on the salivary gland.
The muscarinic receptors are members of
the super family of G-protein coupled receptors.
Binding of Cevimeline to
Muscarinic Receptors
CHO-K cells were transfected
with different human muscarinic receptors
with emphasis on M1, M2, and M3
Relative binding
to transfected receptors
agonists
receptor
M3
(secretory)
M2
(cardiac)
M1
(anti-apoptotic)
pilocarpine
cevimeline
100
100
10
1
1
25
Comparison
•
•
•
•
Cevimeline
3.7 hr half-life in
serum
Longer receptor
occupancy (90 min)
(i.e., IC50)
M3 with little M2
M1 agonist
Pilocarpine
• 1.0 hr half-life in serum
• Short receptor
occupancy (8 minutes)
• Non-selective
• M3 and some M2
(but not clinically a
problem)
Salivation (% max)
and CEV Plasma Concentration
(ng/ml)
90
80
70
60
50
40
30
20
10
0
CEV (ng/ml)
Saliva flow
0
0.5
1
1.5
2
hours
3
4
6
Hints for Successful
Use of Cevimeline in SS - 1
1. Make sure that oral yeast is treated
(probably the most common failure for
expected results)
2. Start cevimeline at 30 mg BID
(preferable 1/2 hr before meals)
Use of Cevimeline in SS - 2
3. After 1-2 wks, may increase to
cevimeline TID
and if tolerated, can use QID.
4. Identify medications (including
herbal or sleeping aids)
with anti-cholinergic properties
and discontinue those.
Use of Cevimeline in SS - 3
5. Sweating may only be transient,
so reassure patient.
6. GI symptoms may also be transient,
thus, consider adding omeprazole
or other proton pump inhibitor.
SUMMARY - 1
1. New diagnostic criteria have been
developed that should diminish confusion
in clinical practice and in the research
literature.
2. Sjogren’s provides a model to study the
interaction of the immune system with the
neural, exocrine, and endocrine systems.
SUMMARY - 2
3. Patients with Sjogren’s have residual
glandular tissue, but it does not
function adequately.
4. Cevimeline provides an opportunity
to explore the new frontiers of
neurobiology.
SUMMARY - 3
5. Both Pilocarpine and Cevimeline
are effective in decreasing symptoms of
dry mouth and oral discomfort.
6. Both Pilocarpine and Cevimeline are
approved by FDA for dry mouth and
further study pending for dry eyes.
SUMMARY - 4
7. Sjogren’s syndrome serves as an
interesting prototype disease
to study the interaction
of immune and neural function
at a site accessible to biopsy.
I am pleased to provide you with
copies of these slides
Please visit our informational website:
http://www.RobertFoxMD.com
Or email me at
[email protected]
Thank you for attending my lecture and
for the honor of meeting with you
谢谢你
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