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

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


1
Diagnosis and Management of Sjogrens
SyndromeLCDR Paul Kruszka, USPHS/USCGPaul.S.Kru
szka_at_uscg.mil
2
What is Sjogrens 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

3
Glossary
  • Xerostomia
  • Xerophthalmia
  • Keratoconjunctivitis sicca KCS
  • Sialadenitis

4
Epidemiology
  • Sjogren Syndrome is the third most common
    autoimmune disease
  • The reported prevalence is between 0.05 and 4.81
  • 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. 200176(6)593-599.

5
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. 200281(4)270-280.

6
Pathogenesis
  • Obscure
  • Primary Sjogren syndrome is associated with
    HLA-DR3 RR 103
  • The histologic hallmark lymphocytic
    infiltration of exocrine glands leading to gland
    degeneration, necrosis, and atrophy4
  • 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 Sjogrens syndrome with
    low-dose human interferon alfa administered by
    the oromucosal route combined phase III
    results. Arthritis Rheum. 200349(4)585-593.

7
Normal Minor Salivary Gland
http//www.siumed.edu/dking2/erg/glands.htmsaliv
8
Minor Salivary Gland Bx
http//en.wikipedia.org/wiki/FileSjogren_syndrome
_(2).jpg
9
Lip biopsy
http//emedicine.medscape.com/article/332125-media
10
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
    fatigue12
  • 5. Kruszka PS and OBrian RJ. Diagnosis and
    Management of Sjogren Syndrome. Am Fam
    Physician. 200979(6)465-470.

11
Extraglandular Manifestations5
12
Physical Exam Findings
  • Conjunctival injection
  • Corneal clouding
  • Decreased salivary pool and dry mucous membranes
  • Dental caries
  • Parotid gland enlargement and tenderness

13
Sjogrens Syndrome Oral Signs
Slide reprinted from the Clinical Slide
Collection on the
14
Sjogrens SyndromeDental Caries Due to Untreated
Dry Mouth
15
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.

16
Frequency of Positive Laboratory Test Results in
Primary Sjogren Syndrome
17
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

18
  • 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

19
Schirmer Test
  • Without anesthesia
  • Measures reflex tear secretion
  • With anesthesia
  • Eliminates stimulated tearing

Permission to use slide granted from Sjogrens
Syndrome Foundation
20
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

21
Differential diagnosis for dry eyes
22
Differential diagnosis for xerostomia
23
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

24
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

25
Keratoconjunctivitis sicca Goals of Treatment
  • Symptom relief
  • Prevention of keratitis, corneal ulceration,
    scarring of the ocular surface

26
Keratoconjunctivitis sicca
  • Topical tear replacement
  • Increasing tear production with stimulation of
    muscarinic receptors
  • Anti-inflammatory medications
  • Punctal occlusion
  • http//health-pictures.com/keratoconjunctivitis-si
    cca.htm

27
OTC eye drops
  • Resources
  • FDA Consumer Magazine
  • http//www.chronicdryeye.com/_articles/Dealing_wit
    h_Dry_Eye.pdf
  • Sjogren Foundation
  • http//www.sjogrens.org/

28
Preservative free eye drops
29
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 Sjogrens syndrome a
    randomized 12 week controlled study. Ann Rheum
    Dis. 200362(12)1204-1207.
  • Ono M, Takamura E, Shinozaki K, et al.
    Therapeutic effect of cevimeline on dry eye in
    patients with Sjogrens syndrome a randomized,
    double-blind clinical study. Am J Ophthalmol.
    2004138(1)6-17.

30
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

31
Muscarinic side effects
  • Sweating
  • Abdominal pain
  • Flushing
  • Increased urination

32
Muscarinic contraindications
  • Asthma
  • Angle closure glaucoma

33
Topical cyclosporine (Restasis)
  • Symptoms of dryness improved (n15)
  • 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.
    200739(1)19-25 (Abstract).

34
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 Apr23(3)249-54.

35
Goals of treatment Xerostomia
  • Alleviate symptoms
  • Prevent complications
  • Dental caries
  • Gum disease
  • Halitosis
  • Salivary gland calculi
  • dysphagia

36
Xerostomia
  • Good oral hygiene
  • Salivary stimulation
  • Saliva substitutes
  • Recognition of complications
  • Daily topical fluoride and antimicrobial mouth
    rinses8
  • Sugar free chewing gum (Xylitol)9
  • Salivary substitutes
  • Ship JA. Diagnosing, managing, and preventing
    salivary gland disorders. Oral Dis.
    20028(2)77-89.
  • Burt BA. The use of sorbitol and
    xylitol-sweetened chewing gum in caries control.
    J Am Dent Assoc. 2006137(2)190-196.

37
Artificial saliva
38
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 Sjogrens Syndrome in
    Taiwan-a double-blind, placebo-controlled trial.
    J Formos Med Assoc. 2006105(10)796-803.
  • Fife RS, Chase WF, Dore RK, et al. Cevimeline
    for the treatment of xerostomia in patients with
    Sjogren syndrome a randomized trial. Arch
    Intern Med. 2002162(11)1293-1300.

39
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 Sjogrens 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 Sogrens syndrome. J Interferon
    Cytokine Res. 199818(4)255-262.

40
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 Schirmers 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. 200450(4)1270-1276.

41
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 sogrens syndrome. Ann. NY
    Acad. Sci. 20091173701-5.

42
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
    Sjogrens Syndrome After Two Infusions of
    Rituximab. Arth. Rheum. 200757(2)310-317

43
Rituximab RCT
  • Double blind RCT
  • 17 patients
  • Significant improvement in fatigue VAS (plt0.001)
  • 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.
    2008671541-1544.

44
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 Sjogrens syndrome.
Rheum 2009481077-1082.
45
Prognosis
  • In comparison to the general Dutch population,
    47 vs. 1.5 received disability compensation
    (plt0.001)12
  • Increased risk of non-Hodgkins lymphoma (NHL)

46
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 lt 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 Sjogrens syndrome a
    cohort study on cancer incidence and lymphoma
    predictors. Ann Rheum Dis. 200665796-803.

47
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 Sjogrens Syndrome. Clinic Rev
    Allerg Immunol 200732292-297.

48
Summary
  • Chronic dry eyes and dry mouth - consider
    Sjogrens 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 Sjogrens syndrome (SORT B)
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