SJOGREN’S SYNDROME Diagnosis and Therapy Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital Scripps/XiMED Medical Center La Jolla (San Diego), California

Learning Objectives List 4 benign manifestations of SS. 2. Identify at least 4 differential diagnoses associated with symptoms that mimic Sjogren’s Syndrome. 3. List 2 ways SS impacts health care costs.

Learning Objectives – 3 4. List 3 approaches to treatment of dry eye and 3 considerations to be aware of when treating dry eyes 5. List 3 approaches to treating dry and painful mouth, and 3 considerations to be aware of when treating it.

Questions we will explore 1.Is it SS or is it SLE? 1.Do we use traditional criteria (American- European) or the new SICCA criteria? 1.How does SS overlap with the newly described IgG4-related disease?

Overview of Therapy addressed in this talk Conservative Therapy Guideline Avoidance of anti-cholinergic medications How to choose artificial tears and saliva How and when to use DMARDs What is the story with biologics

Challenge How can we convey information about treatment of dry eyes/dry mouth to our patients in the limited time allowed in a patient revisit? This is a practical limitation that is very important aspect of patient care.

All slides are available on my website as well as links to treatment of common conditions (oral yeast, etc.) robertfoxmd.com 7

Background-1 Benign manifestations include: 1. Dry and painful eyes 2. Dry and painful mouth 3. Myalgias, fatigue 4. Impaired cognition (executive function)— trying to distinguish “fibromyalgia” from “depression”

Patients would: Equate SS with impact similar to moderate angina. Trade 2 years of “life expectancy” to not have SS symptoms. Dry painful eyes are now the single most common reason for visits to Ophthalmologist

Direct healthcare costs in Great Britain (NHS) are second only to RA, and exceed SLE. RA £2693 (not including TNFs) pSS £2188 (not including OTC cost of artificial tears or dental costs) Age Matched NHS Controls £849 SS-Related Health Care Costs-2:

Diagnosis of Sjogren’s Syndrome European-American Consensus Criteria SICCA Criteria

The European-American Consensus Criteria, 2002 Symptoms of dry eyes and dry mouth –Inability to eat a dry cracker without water. –Water needed at bedside at night. Objective signs of dry eyes and dry mouth (Schirmer’s test, tear break-up) (Saliva flow)

Consensus Criteria, 2002 also called the American-European Consensus Group Criteria (AECG) Evidence of a systemic autoimmune cause for the dryness-- –Positive anti-Ro (SS-A or SS-B antibody) –Positive minor salivary gland biopsy (focus score >1)

You need to be aware There is a recently proposed criteria called the SICCA criteria (described below). The sudden introduction of a new criteria has led to confusion in practice and research.

SICCA Preliminary Criteria (Shiboski, 2012) Requires 2 out of 3 criteria: 1. Positive Anti-SS A/B or ANA >320; 2. Ocular Staining Score >3; 3. Positive labial gland biopsy: focus score >1.

There is about an 82% overlap between the SICCA criteria and the AECC criteria

Does it matter? Our outcome measure ESSDAI was based on old AECC criteria. Literature search and prognosis are all based on old AECC criteria. The 5 published studies comparing both systems indicate IT DOES make a difference.

Now in progress The SICCA criteria will need to be modified Committees are now at work to form a new consensus criteria.

Differential Diagnosis

Is Sjogren’s just SLE with 4/5 SLE Criteria? Different antibody profile (anti-SSA/B) are not criteria for SLE; SS is more organ specific – (salivary/lacrimal gland) and more lymphoproliferative.

Why is Sjogren’s not just SLE with 4/5 Criteria? 1.Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis) 2.Higher frequency of lymphoma 3.Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

Differential Diagnosis of SS-1 SLE-- many similarities to SS RA, Scleroderma, Dermatomyositis-- called secondary Sjogren’s Primary biliary cirrhosis Fibromyalgia with incidental positive ANA

Differential Diagnosis of SS-2 Hepatitis C HIV (AIDS) Tuberculosis –extraglandular Syphilis Lymphoma with positive ANA IgG4-Related Diseases-evolving spectrum

Differential Diagnosis of SS-3 The antibody to Ro (SS-A) or La (SS-B) do not fulfill criteria for SLE. Many older patients labeled with mild SLE actually have SS. Many patients in Hematology clinic with mixed cryoglobulinemia, hemolytic anemia or ITP actually have SS.

Classification-1 Is Sjogren’s just SLE with 4/5 Criteria? Different antibody profile (anti- SSA/B) are not criteria for SLE; SS is more organ specific – (salivary/lacrimal gland) and more lymphoproliferative.

Classification-2 Why is Sjogren’s not just SLE with 4/5 Criteria? 1.Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis) 2.Higher frequency of lymphoma 3.Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

Pathogenesis

Pathogenesis-1 Concordance of SS among identical twins only about 20% Thus, genetic sequence is not enough and over 80% is epigenetic— environmental factor or gene regulation. Distinct histone acetylation pattern upstream of key genes.

Pathogenesis-2 Large sequences of untranslated mRNA. Novel miRNA, some with sequence similar to EBV fragments. Genetics in GWAS recently published and only SS (not SLE) has homing receptor (CXCR5) as a strong “hit.”

To briefly summarize PATHOGENESIS … Acquired Immune System-- HLA DR and Associated T-cell directed B- cell antibodies; IFN-g and IL-17 pathways Innate immune system— Type I IFN signature NK like cells link acquired and innate

Clinical features and treatment

Typical features of dry eyes, dry mouth and swollen glands

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

EYE DRYNESS results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s Syndrome The upper lid literally sticks to the Epithelial surface and pulls surface mucin layers off. The Rose Bengal dye retention test 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

Approach to treatment of benign symptoms a. dry eyes b. dry mouth c. fibromyalgia like symptoms

Normally the upper eyelid glides over the globe on a coating called the tear film composed of water, protein, mucins orbit eyelid Tear film

Treatment-1 Dry eyes 1.For dry eyes, must treat blepharitis before the artificial tears will help. 2.When use ocular lubricant, be sure to use lid scrubs in the morning. 3.Dryeyezone.com for Tranquil Eyes®, wrap-around sunglasses with moisture shields.

Treatment-2 Dry Eyes 4.Do not use preserved artificial tears more than 4x per day. 5.Diurnal rhythm in practice— no Benadryl at night. 6.Particular attention to low-humidity environments of Operating Room and post-op Recovery Room; O 2 administration.

Caution in Sjogren’s Eye A sudden onset of pain and photophobia in only one eye may be a corneal erosion Or it may be herpetic keratitis So beware of the weekend phone call

Severe Xerostomia with dry tongue Angular cheilitis

Treatment of Dry and Painful Mouth 1.Toothpastes (avoid sodium lauryl sulfate) 2.Sugarless mints (Xylimelts®) 3.Mouth Rinses (ACT®) 4.Oral sprays (Oasis®)

Many products on Amazon we urge patients to use SS groups to buy in bulk

Sjogren’s Syndrome- Cervical Dental Caries

Treatment-2 Dry Mouth Considerations 1.Must treat oral candida before secretagogues. 2.Oral yeast can lurk under dentures. 3.Look for angular cheilitis. 4.Treatment may take a month to work.* * This is the type of information for your web page

Treatment-3 Dry and Painful Mouth 1.Cevimeline and pilocarpine—approved by FDA– (only meds actually approved for Sjogren’s) 2. Topical fluoride (help calcification) by dentist at time of frequent cleaning.

Treatment-4 Dry and Painful Mouth 3.MI Paste Is not a toothpaste; it is a topical tooth cream that can be used safely several times daily. Relieves tooth sensitivity. Does not irritate dry mouths caused by certain medications. Helps minimize tooth sensitivity before and after professional cleaning. Helps to minimize tooth sensitivity after whitening procedures. Is helpful during orthodontics relative to helping control (or reduce) dentin hypersensitivity.

Treatment-5 Dry Mouth Considerations 1.Avoid nasal breathing, especially at night. 2.Use nasal lavage to keep down allergic and pollution that cause sinusitis. 3.Be aware of possibility of formation of oral candida after treating for URTI or UTI

Take Home Lesson Dry and Painful Mouth-1 If you thought that Dentists did not care about SS, then wait until you see their Dental Care Plans -- The answer to all problems is a $25,000 tooth implant.

Take Home Point Dry and Painful Mouth-2 Must treat underlying oral candida (which is erythematous spots on roof of mouth) before anything will work. [Candida often lurks under dentures.] Patients would rather run naked through clinic than remove a denture.

Systemic Manifestations and Treatment Considerations 1.Treatment with DMARDs largely the same as SLE. 2.In our experience, Sjogren’s patients do not tolerate Imuran well. 3. MTX used most often to taper steroids. 4. Watch for occult biliary cirrhosis (PBC) or non-alcoholic stator-hepatitis (NASH).

Rash distinct from SLE (erythema annulare)

Hyperglobulemic Purpura

Most Common Skin Manifestations and Treatment in our Clinic 1.Xerosis--Dry skin that requires lubrication 2.We like Anthelosis topical (La Roche Posey available on Amazon), Lachydrin 12, and Eucerin creams 3.Look for livedo reticular, overlap syndromes and Anti-Cardiolipin

Arthritis distinct from RA (Jaccoud’s like)

Arthritis and Sjogren’s May be sero (RF) positive or sero-negative If anti-CCP (+), then consider RA or psoriatic overlap Early onset erosive osteoarthritis Lupus like deformity (Jaccoud’s) in absence of erosion Gout and sepsis still need to be considered in the monoarticular flare

The most difficult aspects of diagnosis and treatment of systemic manifestations in Sjogren’ syndrome: a) lymphoproliferative b) neurologic manifestations

High Risk of Lymphoma

Neurologic Manifestations-1 1.Symmetric peripheral neuropathies most common-unmyelinated small fiber (duloxetene-pregabalin if fail neurontin) 2.Demyelinating (transverse myelitis) and optic neuritis (Devic's) (NMO) (steroids and immune suppressants)

4.Vasculitic –peripheral (mononeuritis multiplex) with steroids, DMARD’s 5. Gangliopathies and plexopathies- may be sensory, motor, autonomic or sudomotor manifestations (steroids, IV-Ig) 6.Thrombotic—cardiolipin (steroids, anti- coagulation) and perhaps rituximab Neurologic Manifestations-2

Overview of treatment of systemic manifestations Steroids work The art of rheumatology is how to taper the steroids

Treatment with DMARDs Hydroxychloroquine—remarkably little data but placebos work Methotrexate and azathioprine— generally lower than RA due to low WBC, mouth ulcers Mycophenolic Acid—less renal than cyclosporine A Rapamycin—I have found this useful

Treatment In SS, several trials of anti-TNF Disappointing with Etanercept, Remicade and other anti-TNF’s. Among RA patients with secondary SS, little improvement in their sicca symptoms.

Previously Studied in SS Anti-CD20 (rituximab) –glandular, extraglandular and fatigue BAFF (Belumimab)-ACR 2012 abstracts* Abatacept (CD40 L)-ACR 2012 Allogeneic mesenchymal cells- ACR 2012 abstracts and article in Blood

Rituximab Remains the most widely used biologic in systemic SS manifestations although not approved It is approved for mixed cryoglob, ITP, and for vasculitis-Wegener’s and MPA (microscopic polyangiitis) It is approved for “rheumatoid” whether seropositive or seronegative.

In practice Rituximab failed double blind studies in both SLE and SS—but it is not given on a regular “basis” like in RA but on an “as needed” basis Rituximab had effect on tears only in early disease and marginal effects on fatigue BAFF has been disappointing and expensive

Other Inhibitors of IFN a. Initial trials of anti-type 1 IFN had infusion reactions and only modest efficacy. b. Medi 546 (type 1 IFN-R antagonists) now in phase 1 (scleroderma) and juvenile SLE phase 2 trial.

SUMMARY-1 The American European Consensus criteria: Subjective symptoms of dryness Objective evidence of autoimmune process such as a positive antibody to SS-A or RF Positive minor salivary gland biopsy

SUMMARY-2 Differential Diagnosis Although SLE is closely related to SS, there are distinct clinical and genetic factors. Think of SLE as immune complex mediated and SS as aggressive lymphocytic infiltrates (including high risk of lymphoma).

SUMMARY-3 Additional Differential Diagnosis include: Hepatitis C and HIV Sarcoidosis, IgG4-related disease Tuberculosis, Syphilis, and Leprosy Fibromyalgia with incidental autoantibodies

SUMMARY-4 Formulate a plan of treatment for benign DRY EYE symptoms— Use of artificial tears and lubricants Punctal occlusion Topical cyclosporin Treat blepharitis

SUMMARY-5 Recognize systemic (extraglandular) sites Rule out infections and begin treatment with DMARDs to spare steroids. DMARDs similar to use in SLE. Hydroxychloroquine Methotrexate, Azathioprine, mycophenolic acid

SUMMARY-6 DMARD Therapy Systemic symptoms- use of DMARDs SLE-like symptoms Rashes including E. annulare and Hyperglobulemic purpura Lymphoma Interstitial pneumonitis and nephritis

But we are still missing key targets in the pathogenesis of fatigue and the adrenal-hypothalmic axis. In both SS and SLE, we can lower the cytokine with biologics, but the patient still feels little improvement. This will be the focus of future direction for therapy.

Thank you for your time and attention We must look at Sjogren’s patients as a challenge to our understanding of the immune interaction with the autonomic and secretory systems. The holy grail for neuro-immunology in the next decade.

T ime course of autoimmune response* 1. Genetic factors predispose to Sjogren’s. 2. Environmental factors such as a viral infection may lead to formation of autoantibodies. 3. Antibodies precede disease (however, presence of antibody does not necessarily mean disease). Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Auto- antibodies Acquired Immune system (HLA-DR) T/B-cells Disease Manifestations * Time period of years Innate Immune system (Toll receptor) Genetic Factors (including sex) (HLA-DR) Environmental Factor (virus-such as EBV ) (apoptotic fragment) Type I IFN Immune complex

The main cytokine targets match those identified in genome wide screens* HLA-DR (T-cell), CTLA and IFN-  NF-K /IkB Homing receptor (CXCR5) Type I IFN –IRF5, STAT4, TLR3/7/9 and pkR (cytoplasmic sensor) B-cell activation –BLK, BAFF, IL12, and A20 (TNFAIP3) * Most of these targets do not map to the encoded protein but to upstream sites of RNA transcription that are not translated (presumed epigenetic sites such as methylation)

SUMMARY-7 Our treatment of fatigue in SS remains unsatisfactory, and represents a great therapeutic challenge for the next decade. Later, we can discuss our approach to this problem in collaboration with Salk Institute and our research institute.

Into the future The immuno-theology of : Danger Signal Hypothesis The immune interaction with neural junctions as the level of the midbrain fMRI Studies in collaboration with Beutler group and Salk Institute

Summary-1 1.Functional circuit needs to be considered when assessing “benign” symptoms of corneal or oral pain. 2.Symptoms of oral/ocular pain do not correlate with markers of systemic inflammation (ESR/CRP) because the events are contained within the brainstem and cortex.

Normal Tearing or Salivation Secretion requires a functional unit mucosal surface gland central nervous system blood vessel afferents efferents lacrimatory or salivatory nuclei water mucin protein water nutrients hormones cortical input

Sjogren’s syndrome affects functional unit ocular surface (cytokines, MMP, growth factor) Gland cytokines, Autoantibodies metalloproteinases central nervous system (HPA axis) blood vessel Chemokines CAMs iNOS lymphocytes Cholinergic efferents adrenergic

Background-3 The Functional Circuit in SS 1. Mucosal Surface (inflammatory cytokines and metalloproteinase) 1. Mucosal Surface (inflammatory cytokines and metalloproteinase) 2. Midbrain Vth Nucleus (lymphocytes and glial cells) 2. Midbrain Vth Nucleus (lymphocytes and glial cells) 4. Gland (lymphs, cytokines, metalloproteinase) 4. Gland (lymphs, cytokines, metalloproteinase) 3. Vascular (iNOS, CAMs, Chemokines) 3. Vascular (iNOS, CAMs, Chemokines) Brain Cortex Nociception (pain) glial cells and corticcal neurons Brain Cortex Nociception (pain) glial cells and corticcal neurons These sites and their cytokines correlate with systemic manifestations We must understand these sites to treat “benign” symptoms.

Thrombospondin (-/-) Mouse at 24 wks. Where a trivial stimuli Causes pain response Wild type A pain stimuli that is innocuous in Wild Type does cause nociceptive pain in tsp (-/-) mouse model. The Pain Threshold is Lowered in the Tsp (-/-) mouse.

To study the mechanism of neurogenic or nociceptive pain we must use animal model-1 The thrombospondin (-/-) mouse (TSP null) or the TGF-  receptor mutation both develop SS like disease. The mouse develops both oral and ocular lesions. The mouse develops ANA and SS-A antibodies.

To study the mechanism of neurogenic or nociceptive pa2n we must use animal model-2 Thrombospondin is a matrix protein that plays a role in activation of latent TGF-  Activated TGF-  promotes Treg and inhibits Th-17 (IFN-  Thus, TSP (null) has high levels of Th-17, IL- 17 and IFN- 

Thrombospondin (-/-) mouse model of SS 4 wks. Lacrimal gland biopsies The mouse has ANA+, SS-A+ TSP null can not activate TGF-  In absence TGF-  continuous Th-17 TGF-  and cytokine activation stimulates mTor/AKT WT Tsp-/- 24 wks

We are also looking at Additional Targets of Interests Chemokines and their receptors (CCR) on vascular cells and lymphocytes TLR receptors: SLAC-15 that links Toll receptor and type 1 IFN Methylation modulators and siRNA Neural mediator circuits: Receptors on cornea--substance P (TRPV1), VIP and CGRP pain receptors TRPM8, TRPA1, and CGRP in trigeminal ganglion neurons Trigeminal ganglion neurons- MCP-1, MIP-2, CCR and CCL at the blood brain barrier

The tsp-null mouse allows us to look at the interaction of peripheral inflammation and microglial cells Activation of microglial cells through mTor/AKT In absence of thrombospondin, constitutive activation of Th17 and IFN-  activates microglial cells Nociceptive (pain) pathway occurs through smad3 and non-smad pathways that involve mTor/AKT pathways in cranial nerve V

Model for stress induction (attach mouse by velcro to stuffed cat)

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 Physiological Similar pattern of Fos-ir in PVH neurons in response to distinct stressors

Thank you for inviting me to participate in this wonderful meeting. We will discuss treatment of dryness of eyes and mouth during afternoon session.

CCR and Blood Brain Barrier