Diagnosis and Management of Sjogren’s Syndrome LCDR Paul Kruszka, USPHS/USCG [email_address]
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
Keratoconjunctivitis sicca : KCS
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
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.
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 http://www.siumed.edu/~dking2/erg/glands.htm#saliv
Minor Salivary Gland Bx http://en.wikipedia.org/wiki/File:Sjogren_syndrome_(2).jpg
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 Manifestations 5 6 Fever not associated with infectious process 6 Renal involvement (proteinuria, renal tubular acidosis, interstitial nephritis, glomerulonephritis, abnormal urinalysis) 7 Lymphadenopathy (cervical, axillary, or inguinal) 7 Peripheral neuropathy 12 Cutaneous vasculitis 16 to 28 Raynaud’s phenomenon 29 Pulmonary disease (chronic cough, recurrent bronchitis with diffuse interstitial infiltrates on radiography, abnormal spirometry, pulmonary alveolitis or fibrosis on computed tomography) 15 to 33 Autoimmune thyroiditis 54 Gastrointestinal symptoms 37 to 75 Arthralgia/non-erosive arthritis characterized by tenderness, swelling, or effusion of peripheral joints frequency Clinical signs/symptoms
Physical Exam Findings
Decreased salivary pool and dry mucous membranes
Parotid gland enlargement and tenderness
Sjogren’s Syndrome Oral Signs Slide reprinted from the Clinical Slide Collection on the
Sjogren’s Syndrome Dental Caries Due to Untreated Dry Mouth
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 32 to 90 Rheumatoid factor 7 to 50 Anti-SSB (La) 16 to 70 Anti-SSA (Ro) 55 to 97 Antinuclear antibody Frequency (%) Tests
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
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
Measures reflex tear secretion
Eliminates stimulated tearing
Permission to use slide granted from Sjogren’s Syndrome Foundation
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 Burning, eyelid swelling/erythema Rosacea Diuretics and anticholinergics. Medications for: Alzheimer's, Parkinson's, allergic rhinitis, depression, incontinence Medications Diminished blinking during long periods of driving, reading, computer Lifestyle Wind, dust, low humidity, irritants Environment Eyelid erythema and crusting, worse in morning, does not respond to eye drops Blepharitis Burning eyes, conjunctival injection, and mucoid secretion Allergic conjunctivitis Comment Condition
Differential diagnosis for xerostomia Non-caseating granulomas in salivary glands Sarcoidosis Mouth breathing Obstructed nasal passages Diuretics and anticholinergics Medications HIV medication Sialadenitis results in 15% of patients with Hep C Hepatitis C External beam radiation damages salivary glands Head and neck radiation Dryness worsens with poor gylcemic control Diabetes Comment Condition
No known cure
Treatment focuses on relieving symptoms and preventing complications
Treatment can be grouped into regimens for
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
Prevention of keratitis, corneal ulceration, scarring of the ocular surface
Topical tear replacement
Increasing tear production with stimulation of muscarinic receptors
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.
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
Angle closure glaucoma
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).
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
Salivary gland calculi
Good oral hygiene
Recognition of complications
Daily topical fluoride and antimicrobial mouth rinses 8
Burt BA. The use of sorbitol and xylitol-sweetened chewing gum in caries control. J Am Dent Assoc. 2006;137(2):190-196.
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.
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)
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.
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.
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
Double blind RCT
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 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. 18(9) Anti-depressants 17(9) Other immunosuppressives 20(10) Rituximab 26(13) Oral corticosteroids 31(16) Anti-malarial drugs 47(24) NSAIDs 18(9) Pilocarpine 20(10) Artificial saliva 46(24) Oral moisturizing gel 151(77) Artificial tears n=195(%) Therapy
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)
16-fold increased risk compared to general population
Prospective study of 508 Swedish patients
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.
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.
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)