Sjogrens Syndrome Evolving Concepts of Treatment based on

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 Robert. Fox. MD@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) 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 i. NOS 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. M 1 receptor (neuroprotective) gland 1. acetyl choline M 3 receptor (regulates water channel) M 3 receptor 2. Acetylcholine released from nerve synapse stimulates M 1 and M 3 receptors nerve

Muscarinic Receptor Actions a) M 1 receptor: neuroprotective and anti-apoptotic properties for neurons b) M 2 receptor: (found on cardiac tissues) c) M 3 receptor: secretory function of gland

Cevimeline (Evoxac) 1. A sterically constrained form of Ach 2. Known in neurochemistry literature as AF 102 b and SN-2011 3. Selected for its M 1 and M 3 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): 12931300. 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. Mc. Millan, 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): 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 gland M 1 receptor mediates glandular resistance to “shock” and facilitate regrowth M 1 cevimeline nerve

Cevimeline actions 1. Stimulates water transport (M 3 receptor) 2 Protects the gland from stress (M 1 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 at least 5 receptors (M 1 -M 5), but we will concentrate on M 1 and M 3 m. ACh. R 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 M 1, M 2, and M 3

Relative binding to transfected receptors agonists receptor M 3 (secretory) M 2 (cardiac) M 1 (anti-apoptotic) pilocarpine cevimeline 100 10 1 1 25

Comparison • • Cevimeline 3. 7 hr half-life in serum Longer receptor occupancy (90 min) (i. e. , IC 50) M 3 with little M 2 M 1 agonist Pilocarpine • 1. 0 hr half-life in serum • Short receptor occupancy (8 minutes) • Non-selective • M 3 and some M 2 (but not clinically a problem)

Salivation (% max) and CEV Plasma Concentration (ng/ml)

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.

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