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

RobertFoxMD@mac.com

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) MGI (Pilocarpine)

b) Daiichi (Cevimeline)

c) Genentech and Amgen

(Etanercept and rituximab)

d) Aventis (leflunomide)

e) 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 - 2Looking 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

Historical1892 - 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)

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.

What is Sjogren’s?

Issues in the patient with true Sjogren’s

1. Treatment of Dry Eyes and Mouth

2. Extent and treatment of

extra glandular Disease• steroids• DMARDs• biologics

3. ReassuranceAnd

Educationencourage patients to access

internet via Google Scholar(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 withcomplaints 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

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 >

We have found brief neuro-psychometric testing

helpful to guide therapy:

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

Sjogren’s NormalLymphocytic

infiltrate

Areas of “lazy” gland

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

orbit

eyelid

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.

orbit

eyelid

Tear film

The Sjogren’spatient is

describingincreased friction

as the upperlid moves

over the globe

Dryness results in the clinical appearance of keratoconjunctivitis sicca (KCS)characteristic of Sjogren’s syndrome

The upper lidliterally sticks to

the surface epithelial surface and pulls

surface mucin layers off. The Rose Bengal

dye retentionis like

“rain water pooling in a street pothole.”

This test can be done at bedside

and allows“triage” and rapid referral of patientsto 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 salivationsecretion requires a functional unit

1. mucosal surface4. gland

Central Nervous System

3. blood vessel

afferentsefferents 2. lacrimatory

or salivatorynuclei inmidbrain

watermucinprotein

waternutrientshormones

corticalinput

Sjogren’s syndrome affects functional unit

1. ocular surface(cytokines, MMP, growth factor)

4. Glandcytokines,

Autoantibodiesmetalloproteinases

2. Central Nervous System

(HPA axis)

3. blood vesselChemokines

CAMsiNOS

lymphocytes

Cholinergicefferents

adrenergic

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

Reasons for glandular dysfunction in Sjogren’s

Acetyl Choline Receptorsof Muscarinic Type 1 and 3

are found on salivary and lacrimal glands

nerve

2. Acetylcholine releasedfrom nerve synapse

stimulatesM1 and M3 receptors

1. acetyl choline M3 receptor

(regulates water channel)

gland

M3 receptor

3. M1 receptor (neuroprotective)

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 CevimelineEfficacy 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. LauClinical Rheumatology 27: 429 (2008)

“The efficacy of cevimeline hydrochloride in thetreatment 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 Taiwanfor 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):796-803.

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

M1

nerve

cevimeline

gland M1M1 receptor mediatesglandular resistance to “shock”and facilitate regrowth

M1

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 Exceloncurrently approved for Alzheimer’s

work to improve memory

by inhibiting acetylcholine esterase

and thus, increasing Ach in the gap

ACh

Acetyl cholinesterase

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 toMuscarinic 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

pilocarpine cevimeline

M3

(secretory)

100 100

M2

(cardiac)

10 1

M1

(anti-apoptotic)

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)

0102030405060708090

0 0.5 1 1.5 2 3 4 6

hours

CEV (ng/ml)

Saliva flow

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.

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.

SUMMARY - 4

I am pleased to provide you with copies of these slides

Please visit our informational website:

http://www.RobertFoxMD.com

Or email me at

RobertFoxMD@mac.com

Thank you for attending my lecture and for the honor of meeting with you

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