Diagnosis and Management of Sjogren

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

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Glossary

• Xerostomia
• Xerophthalmia
• Keratoconjunctivitis sicca KCS
• Sialadenitis

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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.

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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.

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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.

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Normal Minor Salivary Gland
http//www.siumed.edu/dking2/erg/glands.htmsaliv
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Minor Salivary Gland Bx
http//en.wikipedia.org/wiki/FileSjogren_syndrome
_(2).jpg
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Lip biopsy
http//emedicine.medscape.com/article/332125-media
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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.

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Extraglandular Manifestations5
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
Raynauds 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
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Physical Exam Findings

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

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

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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
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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

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• 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

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Schirmer Test

• Without anesthesia
• Measures reflex tear secretion
• With anesthesia
• Eliminates stimulated tearing

Permission to use slide granted from Sjogrens
Syndrome Foundation
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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

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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
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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
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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

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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

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Keratoconjunctivitis sicca Goals of Treatment

• Symptom relief
• Prevention of keratitis, corneal ulceration,
  scarring of the ocular surface

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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

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OTC eye drops

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

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Preservative free eye drops
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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.

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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

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Muscarinic side effects

• Sweating
• Abdominal pain
• Flushing
• Increased urination

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Muscarinic contraindications

• Asthma
• Angle closure glaucoma

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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).

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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.

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Goals of treatment Xerostomia

• Alleviate symptoms
• Prevent complications
• Dental caries
• Gum disease
• Halitosis
• Salivary gland calculi
• dysphagia

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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.

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Artificial saliva
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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.

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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.

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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.

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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.

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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

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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.

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Treatment survey of 195 Dutch patients
Therapy n195()
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 Sjogrens syndrome.
Rheum 2009481077-1082.
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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)

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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.

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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.

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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)