Kruszka - Sjogren_Final2

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Diagnosis and Management of Sjogren’s Syndrome LCDR Paul Kruszka, USPHS/USCG Paul.S.Kruszka@uscg.mil :

Diagnosis and Management of Sjogren’s Syndrome LCDR Paul Kruszka, USPHS/USCG Paul.S.Kruszka@uscg.mil

What is Sjogren’s Syndrome:

What is Sjogren’s Syndrome Systemic autoimmune disease characterized by dry eyes and dry mouth. Other organ systems often affected (extra-glandular manifestations) May be primary - solitary process Secondary disease accompanies another autoimmune disease - most often rheumatoid arthritis or SLE

Glossary:

Glossary Xerostomia Xerophthalmia Keratoconjunctivitis sicca : KCS Sialadenitis

Epidemiology:

Epidemiology Sjogren Syndrome is the third most common autoimmune disease The reported prevalence is between 0.05 and 4.8% 1 A study from Olmsted, MN found physician diagnosed cases to be approximately 4 per 100,000 persons. 1 1. Pillemer SR, Matteson EL, Jacobsson LT, et al. Incidence of physician-diagnosed primary Sjogren syndrome in residents of Olmsed County, Minnesota. Mayo Clin Proc. 2001;76(6):593-599.

Who gets Sjogren Syndrome:

Who gets Sjogren Syndrome A cohort of 400 patients found that the average age of the patients was 52.7 and 93% of the patients were women. 2 An estimated 1 to 2 million Americans have Sjogren Syndrome. 1 Primary vs. secondary 2. Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al. Primary Sjogren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine. 2002;81(4):270-280.

Pathogenesis:

Pathogenesis Obscure Primary Sjogren syndrome is associated with HLA-DR3; RR = 10 3 The histologic hallmark: lymphocytic infiltration of exocrine glands leading to gland degeneration, necrosis, and atrophy 4 Evidence of B cell role: auto-antibodies to self antigens Mitchell RS, Kumar V, Abbas AK, Fausto N. Robbins Basic Pathology 8th edition. Philadelphia 2007. 4. Cummins MJ, Papas A, Kammer GM, Fox PC. Treatment of Primary Sjogren’s syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase III results. Arthritis Rheum. 2003;49(4):585-593.

Normal Minor Salivary Gland:

Normal Minor Salivary Gland http://www.siumed.edu/~dking2/erg/glands.htm#saliv

Minor Salivary Gland Bx:

Minor Salivary Gland Bx http://en.wikipedia.org/wiki/File:Sjogren_syndrome_(2).jpg

Lip biopsy:

Lip biopsy http://emedicine.medscape.com/article/332125-media

Presentation:

Presentation In a prospective cohort study of 400 patients, 98% presented with dry mouth and 93% presented with dry eyes. 2 Associated dry mouth symptoms: difficulty speaking and eating and swallowing, and frequents sips of water. 5 Associated dry eye symptoms: grittiness, dryness, pruritis, foreign body sensation. In one study of 195 Dutch patients, 85% reported fatigue 12 5. Kruszka PS and O’Brian RJ. Diagnosis and Management of Sjogren Syndrome. Am Fam Physician. 2009;79(6):465-470.

Extraglandular Manifestations5:

Extraglandular Manifestations 5 Clinical signs/symptoms frequency Arthralgia/non-erosive arthritis characterized by tenderness, swelling, or effusion of peripheral joints 37 to 75 Gastrointestinal symptoms 54 Autoimmune thyroiditis 15 to 33 Pulmonary disease (chronic cough, recurrent bronchitis with diffuse interstitial infiltrates on radiography, abnormal spirometry, pulmonary alveolitis or fibrosis on computed tomography) 29 Raynaud’s phenomenon 16 to 28 Cutaneous vasculitis 12 Peripheral neuropathy 7 Lymphadenopathy (cervical, axillary, or inguinal) 7 Renal involvement (proteinuria, renal tubular acidosis, interstitial nephritis, glomerulonephritis, abnormal urinalysis) 6 Fever not associated with infectious process 6

Physical Exam Findings:

Physical Exam Findings Conjunctival injection Corneal clouding Decreased salivary pool and dry mucous membranes Dental caries Parotid gland enlargement and tenderness

PowerPoint Presentation:

Sjogren’s Syndrome Oral Signs Slide reprinted from the Clinical Slide Collection on the

PowerPoint Presentation:

Sjogren’s Syndrome Dental Caries Due to Untreated Dry Mouth

Diagnosis:

Diagnosis Diagnosis of primary Sjogren Syndrome is strongly suggested in a patient with: Signs and symptoms of oral ocular dryness Positive antibodies for anti-SS-A and anti-SS-B antigen OR positive salivary gland biopsy Sjogren syndrome often has an insidious onset, a variable course, and a wide spectrum of clinical manifestations, making diagnosis difficult and delayed.

Frequency of Positive Laboratory Test Results in Primary Sjogren Syndrome:

Frequency of Positive Laboratory Test Results in Primary Sjogren Syndrome Tests Frequency (%) Antinuclear antibody 55 to 97 Anti-SSA (Ro) 16 to 70 Anti-SSB (La) 7 to 50 Rheumatoid factor 32 to 90

Revised International Classification Criteria for Sjogren Syndrome:

Revised International Classification Criteria for Sjogren Syndrome Criteria established for homogeneity of research cohorts Provide a useful framework to make a diagnosis The classification requires four of the six items, one of which must be a positive minor salivary gland biopsy or a positive antibody test, or the presence of three of the four objective items

PowerPoint Presentation:

Revised International Classification Criteria for Sjogren Syndrome Ocular symptoms (at least one of the following): daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in eyes, use of tear substitutes more than three time per day Oral symptoms (at least one of the following symptoms): daily feeling of dry mouth for more than three months, recurrent or persistently swollen salivary glands as a adult, need to drink liquids frequently to aid in swallowing dry food. Ocular signs (at least one positive): Schirmer test, Rose Bengal test or other ocular dye test Histopathology (positive biopsy of a salivary gland) Salivary gland involvement (positive results from at least one of the following tests): unstimulated whole salivary flow collection (less than 1.5ml in 15 minutes); parotid sialography showing the presence of diffuse sialectasia; Salivary scintigraphy showing delayed uptake, reduced concentration and delayed excretion of tracer Presence of Anti-SSA and Anti-SSB

PowerPoint Presentation:

Schirmer Test Without anesthesia Measures reflex tear secretion With anesthesia Eliminates stimulated tearing Permission to use slide granted from Sjogren’s Syndrome Foundation

Non-stimulated whole saliva flow :

Non-stimulated whole saliva flow Spit into graduated test tube every minute for 15 minutes. Collection of less than 1.5mL in 15 minutes is considered positive

Differential diagnosis for dry eyes:

Differential diagnosis for dry eyes Condition Comment Allergic conjunctivitis Burning eyes, conjunctival injection, and mucoid secretion Blepharitis Eyelid erythema and crusting, worse in morning, does not respond to eye drops Environment Wind, dust, low humidity, irritants Lifestyle Diminished blinking during long periods of driving, reading, computer Medications Diuretics and anticholinergics. Medications for: Alzheimer's, Parkinson's, allergic rhinitis, depression, incontinence Rosacea Burning, eyelid swelling/erythema

Differential diagnosis for xerostomia:

Differential diagnosis for xerostomia Condition Comment Diabetes Dryness worsens with poor gylcemic control Head and neck radiation External beam radiation damages salivary glands Hepatitis C Sialadenitis results in 15% of patients with Hep C HIV medication Medications Diuretics and anticholinergics Obstructed nasal passages Mouth breathing Sarcoidosis Non- caseating granulomas in salivary glands

Treatment :

Treatment No known cure Treatment focuses on relieving symptoms and preventing complications Treatment can be grouped into regimens for General measures KCS Xerostomia Systemic manifestations

General Measures :

General Measures Avoidance of drugs that worsen sicca symptoms Avoidance of low humidity environments Use of humidifiers Avoid dust and cigarette smoke Good oral hygiene

Keratoconjunctivitis sicca: Goals of Treatment:

Keratoconjunctivitis sicca: Goals of Treatment Symptom relief Prevention of keratitis, corneal ulceration, scarring of the ocular surface

Keratoconjunctivitis sicca:

Keratoconjunctivitis sicca Topical tear replacement Increasing tear production with stimulation of muscarinic receptors Anti-inflammatory medications Punctal occlusion http://health-pictures.com/keratoconjunctivitis-sicca.htm

OTC eye drops:

OTC eye drops Resources FDA Consumer Magazine http://www.chronicdryeye.com/_articles/Dealing_with_Dry_Eye.pdf Sjogren Foundation http://www.sjogrens.org/

Preservative free eye drops:

Preservative free eye drops

Muscarinic agonists (SORT B):

Muscarinic agonists (SORT B) Oral pilocarine (Salagen) at a dosage of 5mg twice daily has been shown in a small RCT to decrease subjective eye symptoms and improve results of rose Bengal testing Oral cevimeline (Evoxac) at a dosage of 30mg three times daily relieved subjective eye symptoms in another small RCT. Tsifetaki N, Kitsos G, Paschides CA, et al. Oral pilocarpine for the treatment of ocular symptoms in patients with Sjogren’s syndrome: a randomized 12 week controlled study. Ann Rheum Dis. 2003;62(12):1204-1207. Ono M, Takamura E, Shinozaki K, et al. Therapeutic effect of cevimeline on dry eye in patients with Sjogren’s syndrome: a randomized, double-blind clinical study. Am J Ophthalmol. 2004;138(1):6-17.

SORT:

SORT A = consistent, good-quality patient-oriented evidence B = inconsistent or limited-quality patient-oriented evidence C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series

Muscarinic side effects :

Muscarinic side effects Sweating Abdominal pain Flushing Increased urination

Muscarinic contraindications:

Muscarinic contraindications Asthma Angle closure glaucoma

Topical cyclosporine (Restasis):

Topical cyclosporine (Restasis) Symptoms of dryness improved (n=15) No change in Schirmer test Jain AK, Sukhija J, Dwedi s, Sood A. Effect of topical cyclosporine on tear functions in tear-deficient dry eyes. Ann Ophthalmol. 2007:39(1):19-25 (Abstract).

Punctal Plugs:

Punctal Plugs Temporary or permanent silicone Improves rose bengal staining scores No change in Schirmer values Sakamoto A, Kitagawa K, Tatami A. Efficacy and retention rate of two types of silicone punctal plugs in patients with and without sjogren syndrome. Corea. 2004 Apr;23(3):249-54.

Goals of treatment: Xerostomia:

Goals of treatment: Xerostomia Alleviate symptoms Prevent complications Dental caries Gum disease Halitosis Salivary gland calculi dysphagia

Xerostomia:

Xerostomia Good oral hygiene Salivary stimulation Saliva substitutes Recognition of complications Daily topical fluoride and antimicrobial mouth rinses 8 Sugar free chewing gum (Xylitol) 9 Salivary substitutes Ship JA. Diagnosing, managing, and preventing salivary gland disorders. Oral Dis. 2002;8(2):77-89. Burt BA. The use of sorbitol and xylitol-sweetened chewing gum in caries control. J Am Dent Assoc. 2006;137(2):190-196.

Artificial saliva:

Artificial saliva

Muscarinic agonists in xerostomia:

Muscarinic agonists in xerostomia Pilocarpine: a small RCT of 44 patients showed 5mg four times daily improved subjective xerostomia. 10 Cevimeline: 30mg three times daily improved symptoms and salivary flow. 11 Wu CH, Hsieh SC, Lee KL, Li KJ, Lu MC, Yu CL. Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sjogren’s Syndrome in Taiwan-a double-blind, placebo-controlled trial. J Formos Med Assoc. 2006;105(10):796-803. Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treatment of xerostomia in patient’s with Sjogren syndrome: a randomized trial. Arch Intern Med. 2002;162(11):1293-1300.

Interferon alpha :

Interferon alpha Improvement in subjective oral and ocular dryness and an increase in non-stimulated whole saliva flow. 13 A smaller study showed improvement in histologically normal-appearing minor salivary gland lip biopsies. 14 Cummins MJ, Papas A, Kammer GM, Fox PC. Treatment of primary Sjogren’s syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase III results. Arthritis Rheum 2003; 49(4):585-593. 14. Shiozawa S,, Tanaka Y, Shiozawa K. Single-blinded controlled trial of low-dose oral IFN-alpha for the treatment of xerostomia in patients with Sogren’s syndrome. J Interferon Cytokine Res. 199818(4):255-262.

Anti-Tumor Necrosis Factor (anti-TNF):

Anti-Tumor Necrosis Factor (anti-TNF) Varied results Largest RCT of 103 patients treated with Remicade Evaluated at 10 and 22 weeks No change in subjective oral/ocular dryness No objective improvement: Schirmer’s test or focus score on labial salivary gland biopsy Mariette X, Ravaud P, Steinfeld S, et al. Inefficacy of infliximab in primary Sogren syndrome: results of the randomized controlled Trial of Remicade in Primary Sjogrens Syndrome (TRIPSS). Arthritis Rheum. 2004;50(4):1270-1276.

Rituximab:

Rituximab Chimeric monoclonal antibody Targets B lymphocyte antigen CD20 Case reports and pilot studies show successful treatment of SS with Rituximab Alcantara C, Gomes MJ, Ferreira C. Rituximab Therapy in Primary sogren’s syndrome. Ann. NY Acad. Sci. 2009;1173:701-5.

Rituximab Treatment:

Rituximab Treatment Open label study of 16 patients 36 week follow-up Subjective improvements in disease activity and quality of life. Depletion of B cells in blood and salivary gland biopsy Devauchelle-Pensec V, Pennec Y, Morvan J, Pers J, Daridon Cousse-Joulin S. Improvement of Sjogren’s Syndrome After Two Infusions of Rituximab. Arth. Rheum. 2007;57(2):310-317

Rituximab RCT:

Rituximab RCT Double blind RCT 17 patients Significant improvement in fatigue VAS (p<0.001) Dass S, Bowman s, Vital EM et al. Reduction of fatigue in Sjogren syndrome with rituximab: results of a randomised, double-blind placebo controlled pilot study. Ann. Rheum. Dis. 2008;67:1541-1544.

Treatment survey of 195 Dutch patients:

Treatment survey of 195 Dutch patients Therapy n=195(%) Artificial tears 151(77) Oral moisturizing gel 46(24) Artificial saliva 20(10) Pilocarpine 18(9) NSAIDs 47(24) Anti-malarial drugs 31(16) Oral corticosteroids 26(13) Rituximab 20(10) Other immunosuppressives 17(9) Anti-depressants 18(9) 12. Meijer JM, Meiners PM, Huddleston JR, Spijkervet FK, Kallenberg CG, Vissink A et al. Health-related quality of life, employment and disability in patients with Sjogren’s syndrome. Rheum 2009;48:1077-1082.

Prognosis:

Prognosis In comparison to the general Dutch population, 47% vs. 1.5% received disability compensation (p<0.001) 12 Increased risk of non-Hodgkins lymphoma (NHL)

NHL:

NHL 16-fold increased risk compared to general population Prospective study of 508 Swedish patients Significant predictors: Purpura/skin vasculitis (HR 4.64(1.13-16.45)) Low C3 (HR 6.18(1.57-24.22)) Low C4 (HR 9.49(1.94-46.54)) CD4+ lymphocytopenia (HR 8.14, 2.10-31.53)) Low CD4+/CD8+ ratio < 0.8 (HR 10.92,2.80-41.83)) Theander E, Henriksson G, Ljungber O, Mandl T, Manthorpe R, Jacobs LT. Lymphoma and other malignancies in primary Sjogren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65:796-803.

Future direction:

Future direction Anti-CD22 (Epratuxumab) Anti-BAFF (B cell-activating factor) Meijer JM, Pipe J, Bootsma H, Vissink A, Kallenber CG. The Future of Biologic Agents in the Treatment of Sjogren’s Syndrome. Clinic Rev Allerg Immunol 2007;32:292-297.

Summary:

Summary Chronic dry eyes and dry mouth - consider Sjogren’s Syndrome Muscarinic agonists improve subjective and objective signs and symptoms of xerostomia (SORT B) Interferon alpha improves subjective oral and ocular dryness and increases nonstimulated saliva flow in patiens with Sjogren’s syndrome (SORT B)

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