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_address]
Acknowledgements Carla Fox, R.N. Clinical Coordinator and Medical Editor Scripps Memorial Hospital and Research Foundation Karin Tatsumoto, M.D. Daiichi Sankyo Tokyo, Japan
I have worked as Principal Investigator in multicenter trials for:
Genentech and Amgen
(Etanercept and rituximab)
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:
where dryness is present due to
cholinergic outflow imbalance?
Take Home Lesson - 1
Sjogren’s is characterized by dry eyes and dry mouth due to lymphocytic infiltrates in the glands.
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
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.
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)
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
extra glandular Disease
3. Reassurance And Education encourage 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:
2. Patient with
Dryness and Fibromyalgia
but little else to suggest SS
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
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 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 Normal Lymphocytic 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’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 1. mucosal surface 4. gland Central Nervous System 3. blood vessel afferents efferents 2. lacrimatory or salivatory nuclei in midbrain water mucin protein water nutrients hormones cortical input
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
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:
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 Sjren'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 M1 M1 receptor mediates glandular resistance to “shock” and facilitate regrowth M1
Stimulates water transport (M3 receptor)
Protects the gland from stress (M1 receptor)
Up regulates new proteins (defensins/histatins)
Alters post translational modification of salivary proteins
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 ACh Acetyl cholinesterase
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.
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