SJOGREN’S SYNDROME: Diagnosis and Therapy Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital Scripps/XiM Medical Center La Jolla, California USA robertfoxmd@mac.com

Learning Objectives: By the end of the session, the participant will be able to: the participants should be able to: Define the European criteria for diagnosis of Sjogren’s Syndrome (SS) Symptoms of dry eyes and mouth Objective evidence of autoimmunity: (either a SS-A/SS-B or a positive lip biopsy)

Learning Objectives List 2 glandular manifestations of SS. Dryness of eyes or mouth Lymphoproliferation or lymphoma of lacrimal or salivary glands involvement with SS presentations.

Learning Objectives Describe at least 4 sites of extraglandular involvement in Sjogren’s syndrome Skin-vasculitis Lungs-interstitial pneumonitis or BALT Kidneys-interstitial nephritis Neurologic-peripheral or central

Learning Objectives Identify at least 3 differential diagnoses that are difficult to distinguish from Sjogren’s Syndrome. SLE—altho they often co-exist, there are differences IgG4-related disease. This is a newly defined comples of diseases Idiopathic Neurologic disorders with an incidental SS-A

All slides are available on my website robertfoxmd.com 6

SS has “benign” and “systemic” Background-1 SS has “benign” and “systemic” manifestations.

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

SS Related Health Care Costs-1: Dry or painful eyes are now most common cause of visits to Ophthalmologists in U.S. and Japan. Lost productivity (over $160 billion/year just for dry eyes (especially in computer users where decreased blink rate is 90%.

Sjogren’s symptoms are so debilitating, that patients would: equate SS with impact similar to moderate angina. trade 2 years of “life expectancy” to not have SS symptoms.

SS-Related Health Care Costs-2: 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-3: Despite these costs of health care, patient and physician dissatisfaction with clinical outcomes is higher in pSS than in SLE or RA.

Diagnosis of Sjogren’s Syndrome

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)

Most important “child” of AECC was the ESSDAI (European Sjogren’s Syndrome Activity Index) which includes 16 domains of activity score including glandular and extraglandular activity The ESSDAI ranges from 1-130 Practically, the range is 1-41 A clinically meaningful change is 3.5 units Constitutional Skin Lung, Renal Neurologic

ESSDAI- European SS Activity Index Weighted domains to give a total score— the Sjogren’s equivalent to ACR-50 for RA. The validated ESSDAI activity score has been the accepted outcome measure of FDA clinical trials.

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. The SICCA criteria will need to be modified, and committees are now at work to form a new consensus criteria.

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

Clinical Manifestations Benign -- glandular dryness Systemic -- extraglandular

Clinical Key Points : Dry Mouth

literally sticks to the 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

Rash distinct from SLE (erythema annulare)

Arthritis distinct from RA

High Risk of Lymphoma

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 Leprosy 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.

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? Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis) Higher frequency of lymphoma Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

Lymphoma and Type II mixed cryoglobulinemia

Lymphocytic Interstitial Pneumonitis Bi-basilar on CXR Prominent Cystic on CAT Lymphocytes on biopsy

Transverse Myelitis Neuromyelitis Optica DeVic’s Syndrome: Transverse Myelitis Neuromyelitis Optica

Lymphocytic Interstitial Nephritis

Pathogenesis-1 Genetics Environmental Factors Cytokines of innate and acquired immune system

Pathogenesis-2 only about 20%. 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-3 Novel miRNA, some with sequence similar 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.”

Pathogenesis-4 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

Time course of autoimmune response. 1 Time 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). Innate Immune system (Toll receptor) Environmental Factor (virus-such as EBV) (apoptotic fragment) Auto- antibodies Immune complex Type I IFN Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Disease Manifestations Acquired Immune system (HLA-DR) T/B-cells * Time period of years

The main cytokine targets match those identified in genome wide screens* HLA-DR (T-cell), CTLA and IFN-g 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)

Pathogenesis-5 Genome-Wide Association Parallels-- our studies on cytokine profiles Strongest is HLA-DR and acquired immune system leading to T-cell/B-cell production of autoantibody. Next strongest are Innate Immune markers associated with Type 1 IFN production. As noted above, also find a homing receptor (CXCR5) which goes with the tissue-specific homing receptors. In SS patients with lymphoma, find A20 (member of TNF superfamily) that suppresses NFK-b and B-cell proliferation.

Treatment of DRY EYE Benign Symptoms-1 Artificial tears and lubricants Punctal occlusion Do not use preserved tears more than 4x/day Topical cyclosporin (Restasis) Recognize and treat blepharitis

DRY EYE Therapy-2 Special needs in operating room (low humidity and high risk corneal abrasion) Avoid Lasik eye surgery Look for “lid lag” and exposure zone keratopathy.

Treatment of DRY MOUTH-1 Artificial Saliva, mouth rinses and sprays Secretagogues-pilocarpine and cevimeline Fluoride to prevent caries Treat oral candida (often under dentures)

Treatment of DRY MOUTH-2 Avoid medications with anti-cholinergic side effects (esp. over the counter medications at night) such as Benadryl or amitryptilline. Keep nasal passages open to avoid mouth breathing. Recognize gastric reflux at night (laryngo-tracheal reflux)

Patient Education Time does not permit patient education at time of office visit. Create and use an internet site for common questions about treatment. Feel free to use information from my website for your patients.

Systemic Manifestations Steroids work but have side effects. DMARDs to taper or replace steroids. Hydroxychloroquine Methotrexate, Azathioprine Mycophenolic acid mofetil We are interested in Sirolimus (rapamycin)

Biologics Previously Studied in SS Anti-CD20 (rituximab)* –glandular swelling, extraglandular renal and lung, mixed cryoglobulinemia BAFF (Blys)-ACR 2012 abstracts has been disappointing Abatacept (CD40 L)-ACR 2012

Rituximab Most widely used biologic in SS (ACR 2013 abstracts). Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia. Not approved by FDA.

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.

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

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.

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Summary-1 Functional circuit needs to be considered when assessing “benign” symptoms of corneal or oral pain. 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.

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.

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.

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.

Dry and Painful Mouth-3 Angular cheilitis the most obvious hint. Treatment of oral candida is a slow process involving multiple steps. Use website for education.

We are also looking at additional targets of interest 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

CCR and Blood Brain Barrier

Activation of microglial cells through mTor/AKT 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-g activates microglial cells Nociceptive (pain) pathway occurs through smad3 and non-smad pathways that involve mTor/AKT pathways in cranial nerve V

Thank you for inviting us. Robert I. Fox, M.D., Ph.D. http://www.robertfoxmd.com RobertFoxMD@mac.com