* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download - Dr. Robert Fox
Survey
Document related concepts
Behçet's disease wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Innate immune system wikipedia , lookup
Myasthenia gravis wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Autoimmune encephalitis wikipedia , lookup
Multiple sclerosis research wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Management of multiple sclerosis wikipedia , lookup
Rheumatoid arthritis wikipedia , lookup
Systemic lupus erythematosus wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Transcript
Sjogren’s Syndrome: Diagnosis and Therapy Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital Scripps/XiMED Medical Center La Jolla, California [email protected] Learning Objectives - 1: By the end of the session, the participant will be able to: 1)Definethe and apply the European participants should be criteria able to: for diagnosis of Sjogren’s Syndrome (SS). 2)Identify and compare at least 3 other diseases in the differential diagnosis of SS. Learning Objectives - 2: 3) List 4 benign manifestations of SS. 4) List 2 ways SS impacts health care costs. 3) Describe at least 4 sites of extraglandular involvement with SS presentations. Learning Objectives – 3 4) Identify 3 elements associated with heightened risk of lymphoma in Sjogren’s patients. 5) Identify 2 diagnostic tests to evaluate objective signs of dry eyes and dry mouth. Learning Objectives - 4 6) Identify at least 5 differential diagnoses associated with Sjogren’s Syndrome. 7) Identify 3 preliminary SICCA criteria. 8) List at least 3 elements of treatment: a) for the patient with “benign” symptoms; b) for the patient with extraglandular manifestations. Learning Objectives – 4 \ 9) Identify 2 elements each related to the pathogenesis of the Innate and Acquired immune systems. 10) List 8 elements of the treatment of dry eye and 7 elements of the treatment of dry mouth. All slides are available on my website robertfoxmd.com 7 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 Costs1: • Dry or painful eyes are now most common cause of visits to Ophthalmologists in US and Japan. • Lost productivity (over $160 billion/year just for dry eyes (especially in computer users where decreased blink rate is 90%. 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 by bed at night • Objective signs of dry eyes and dry mouth (Schirmer’s test, tear break up) (Saliva flow) Consensus Criteria, 2002 (Also called the AmericanEuropean Consensus Criteria) • 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: 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. Clinical Manifestations • Benign—glandular dryness • Systemic--extraglandular Clinical Key Points : Dry Mouth 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 • SLE-many similarities to SS • RA, Scleroderma, Dermatomyositis-called secondary Sjogren’s • Primary biliary cirrhosis • Fibromyalgia with incidental positive ANA Differential Diagnosis • • • • • • • Hepatitis C, HIV (AIDS), Tuberculosis, Leprosy, Syphilis Lymphoma with ANA positive IgG4-Related Diseases-evolving spectrum Is Sjogren’s just SLE with 4/5 SLE Criteria? • Different antibody profile (antiSSA/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 • 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 Pathogenesis - 1 • Genetics • Environmental Factors • Cytokines of innate and acquired immune system Pathogenesis-2 • 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 • 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 Bcell 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. 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). Environmental Factor (virus-such as EBV) (apoptotic fragment) Innate (Toll receptor) Type I IFN Genetic Genetic Genetic Genetic Factors Factors Factors Factors (including (including (includingsex) sex) sex) (HLA-DR) (HLA-DR) (HLA-DR) (HLA-DR) Autoantibodies Immune system Immune complex Acquired Immune system (HLA-DR) T/B-cells Disease Manifestations * 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 • • • • • 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 • 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 • • • • Artificial Saliva, Mouth Rinses and Sprays Secretagogues-pilocarpine and cevimeline Fluoride to prevent caries Treat oral candida (often under dentures) Dry Mouth • 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 (laryngotracheal 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 own 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 Learning Objectives-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 Learning objective: 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 Learning Objectives-2 Additional Differential Diagnosis include • Hepatitis C and HIV • Sarcoidosis, IgG4-related disease • Tuberculosis, Syphilis, and Leprosy • Fibromyalgia with incidental autoantibodies Summary Learning Objective-4 • Formulate a plan of treatment for benign symptoms – – – – Use of artificial tears and lubricants Punctal occlusion Topical cyclosporin Treat blepharitis Summary Learning Objective: 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 Learning Objectives Therapy • Systemic symptoms-use of DMARDs – – – – – SLE like symptoms Rashes including E. annulare and Hyperglobulemic purpura Lymphoma Interstitial pneumonitis and nephritis Summary • 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 Thank you for your time and attention • شكرا لك على لطفك واالهتمام 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. 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 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 [email protected]