Sjogren's Syndrome (SJS)

Contributor: Amy C. Cannella, MD

CASE 1

A previously healthy 32 year-old woman presents with complaints of six months of worsening dry eyes and dry mouth. She feels a gritty sensation in her eyes, and has been unable to wear her contact lenses. She states her dentist is concerned because she has developed multiple dental caries. She also feels some fullness in her cheeks. She has been very fatigued and achy. Her physical exam reveals dry mucous membranes, dental caries at the gum line and swelling in her parotid glands. A Shirmer's test is done and results in 3 mm of bilateral tear wetting in 5 minutes. The remainder of the examination is normal. Laboratory testing is done and the ANA is 1:640 (by immunofluorescence), and the anti-Ro (SSA) and anti-La (SSB) antibodies are strongly positive. A diagnosis of primary Sjogren's syndrome (SS) is made.

What are the key features that lead to a diagnosis of SS?

Patients with primary SS commonly present with sicca symptoms (dryness), both ocular and oral. Persistent dry eyes and/or dry mouth (daily for over three months), without an alternative explanation are very important clues in this diagnosis. Patients describe a sandy or gravel sensation in their eyes. In addition to dryness (xerostomia), common oral complaints include salivary gland swelling, an increase in dental caries at the gum-line, and the need to use liquid to aid in swallowing or awakening at night to drink.

Ocular signs, such as a positive Schirmer's test can help give objective evidence for ocular dryness. A Schirmer's test can be done in the office and consists of gently placing sterile filter paper between the eye and the lower lid and measuring tear production. A positive test result is < 5 mm of wetting in 5 minutes. Additional tests include an ocular staining score (OSS), which involves fluorescein staining of the cornea and lissamine green staining of the bulbar conjunctivae for a total score ranging from 0-12 (> 3 is positive), and a tear breakup time (TBUT) of<10 seconds. Rose Bengal staining can be used to assess conjunctival and corneal damage in patients with sicca, but it is toxic to the epithelial cells and painful to patients.

Tests can also be done for xerostomia. These include salivary gland scintigraphy, which gives a dynamic measure of salivary gland function by looking at radiotracer uptake, and unstimulated whole salivary flow (UWS) which measures the rate of saliva production.

The presence of antibodies to Rheumatoid Factor (RF), ANA, Ro (SS-A) and La (SS-B) are commonly found in patients with primary SS. Multiple studies have reported differing frequencies, but in general the presence of one or more of these antibodies are seen in over half of affected patients.

A minor salivary gland biopsy is done with a punch biopsy of the lower lip to support a diagnosis of SS. A scoring system is employed by the pathologist, looking for focal lymphocytic sialadenitis (FLS), and a score of > 1 is considered positive.

CASE 2

A 56 year old woman with a past medical history of hypertension presents with palpable purpura on her lower legs, and a painful sensation in her right foot with the inability to dorsiflex the foot. She also describes a painful triphasic color change in her fingers upon cold exposure, consistent with Raynaud’s phenomenon. With further questioning, she states she has had years of dry eyes and dry mouth. On physical examination, she is edentulous, has dry mucous membranes, has palpable purpura on her lower legs and has a right foot drop. Her Shirmer’s test results in 1 mm of bilateral tear wetting in 5 minutes. Her ANA, Rheumatoid factor, anti-Ro (SSA) and anti-La (SSB) are strongly positive. Other serologies are negative. She has positive cryoglobulins and a monoclonal protein on serum protein electrophoresis. A minor salivary gland biopsy is done and shows a focus score of > 1. A sural nerve biopsy shows vasculitis. A diagnosis of Sjogren’s syndrome with vasculitis is made.

What additional extra-glandular manifestation of Sjogren’s Syndrome is concerning in this case?

This patient has likely had long-standing SS, which places her at risk for the development of Non-Hodgkins Lymphoma (NHL). The lifetime risk for developing NHL in SS is 5-10%, which is markedly higher than that of the general population. Risk factors for the development of NHL include the length of time with the disease, a low C4, presence of type II cryoglobulins, anemia, lymphocytopenia, hypergammaglobulinemia, cutaneous vasculitis (palpable purpura), lymphadenopathy, splenomegaly, parotid enlargement and peripheral neuropathy. Patients with SS will have a monoclonal gammopathy up to 22% of the time, and it may be a harbinger of NHL. In this case, the monoclonal gammopathy, vasculitis, serologic positivity and cryoglobulinemia warrant a referral to hematology for evaluation for lymphoma.

Patient Care

  1. Identify common patient complaints suggestive of the diagnosis of SS, including both oral (xerostomia) and ocular (xerophthlalmia) symptoms and glandular swelling.
  2. Recognize that patients with xerostomia may have problems with chewing and swallowing food, dental caries (at the gum line) and oral candidiasis.
  3. Consider the differential diagnosis for sicca symptoms and evaluate the patient for diseases which mimic SS, such as HIV, HCV, sarcoidosis and lymphoma.
  4. Recognize the association of SS with other autoimmune conditions, including RA, scleroderma and SLE.
  5. Identify the visceral manifestations of SS and the significant morbidity for patients with end-organ involvement.
  6. Identify comorbid conditions that can worsen sicca symptoms in SS, such as smoking, medications and vitamin deficiency.
  7. Recognize the different treatment approaches for glandular and extra glandular manifestations of Sjogren's syndrome.

Medical Knowledge

  1. Identify the epidemiology of SS, including primary and secondary forms.
  2. Recognize the pathogenic mechanisms, including genetic and environmental factors that may lead to the development of Sjogren’s syndrome.
  3. Distinguish the lacrimal and salivary glandular pathology of focal lymphocytic infiltration involved with oral and ocular symptoms of the disease.
  4. Identify and extra-glandular manifestations of the disease, including arthritis, pulmonary disease, distal renal tubular acidosis, thyroiditis, hepatitis, neuropathy and cutaneous vasculitis.
  5. Identifythe importance of auto-antibodies in SS, including nonspecific ANA and RF and more specific anti-Ro and anti-La.
  6. Describe the commonly used tests for the diagnosis of SS, including a minor salivary gland biopsy, Schirmer’s test, and ocular staining score.
  7. Recognize the risk of developing lymphoma in SS, and the associated harbingers of malignancy (reduction of RF titer, glandular swelling).

Interpersonal and Communication Skills

  1. Discuss the disease and potential complications with patients in a way that incorporates patients’ perspectives.
  2. Utilize the electronic health record to promote patient centered communication.
  3. Utilize web based resources to help educate patients about SS.
  4. Outline a non-pharmacologic treatment regimen for different facets of SS.
  5. Outline a targeted pharmacologic treatment regimen and understand the side effects of therapy.
  6. Recognize the impact of SS on pregnancy outcomes and develop a plan to discuss this with patients.

Professionalism

  1. Recognize the effects of a chronic disease on the patient, the family and quality of life.
  2. Recognize the importance of patient privacy, informed consent and equal care.
  3. Provide adequate time and accessibility to address patient concerns.
  4. Demonstrate integrity and honesty in discussing patient care issues and management with the patient and family.

Practice Based Learning

  1. Identify the evolving nature of classification criteria and distinguish the use of these criteria for clinical trials and as diagnostic aids in clinical practice. Recognize the two classification criteria for SS: 1) the 2002 American-European Consensus Group Classification Criteria for Sjogren’s Syndrome and 2) the 2012 American College of Rheumatology Classification Criteria.
  2. Integrate and apply information from the history and physical, laboratory and diagnostic testing to make informed decisions about patient care.
  3. Set learning goals in SS diagnosis and management.
  4. Utilize web-based resources for the most current information (1, 2) on diagnosis and treatment of SS.
  5. Recognize the importance of workplace assessments and develop a willingness to adapt and apply changes based on feedback.

System Based Practice

  1. Recognize that the diagnosis can be challenging and referral to a rheumatologist is helpful.
  2. Recognize the need for interdisciplinary management, including close follow-up with ophthalmology and dental providers.
  3. Identify barriers to the delivery of optimal patient care for patients with SS and offer improved ideas for delivering care.
  4. Identify patient barriers to the treatment plan and be sensitive to both cultural and financial obstacles in delivering patient care.
  5. Demonstrate an awareness of the impact of diagnostic and pharmacologic recommendations on the health care system, including insurance companies, physician and patient.

References

Questions

(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom of this page.)

  1. Which of the following objective measures have been shown to have the greatest sensitivity and specificity when used in combination for the diagnosis of SS?
  2.  

    1. Anti-Ro or La antibody, Ocular Staining Score (OSS) and Minor Salivary Gland biopsy
    2. Rheumatoid Factor, Shirmer’s test, Unstimulated Whole Salivary Flow (UWS)
    3. Anti-Ro or La antibody, Tear Breakup Time and Shirmer’s test
    4. Anti-Ro or La antibody, Unstimulated Whole Salivary Flow (UWS) and Salivary Scintigraphy
    5. Anti- Ro or La antibody, ANA, and Shirmer’s Test

     

  3. You are taking care of the following patients with SICCA. In which patient are you most concerned about the development of lymphoma?
  4.  

    1. A 25 year old woman with dry eyes and dry mouth, low titer anti-Ro and fatigue.
    2. A60 year old edentulous male with a history of squamous cell carcinoma of the tongue. He continues to smoke heavily. He has negative serologies and had radiation for his previous tongue cancer.
    3. A 70 year old edentulous woman with high titer anti-Ro antibodies, parotid enlargement, and palpable purpura on her legs.
    4. A 50 year old Black man male with hilar lymphadenopathy and a painful rash on his shins.
    5. A 35 year old woman with seropositive RA, and positive anti-Ro antibody, who is no longer able to wear her contact lenses.

     

  5. You are following a 30 year old woman with known SS. She complains today of muscle weakness and myalgia. Two weeks ago, she was started on hydroxychloroquine 400 mg daily. Based on her laboratory findings below, what is the most likely finding on a kidney biopsy?
  6.  

    Potassium = 2.0 mEq/L (normal 3.6 to 5.1 Eq/L)
    Bicarbonate = 6.0 Eq/L (normal 22 to 32 Eq/L)
    Creatinine = 0.8 mg/dL (normal 0.64 to 1.27 mg/dL)
    Urine pH = 8
    Urinalysis: trace blood and no protein

    1. Membranous Nephropathy
    2. Interstitial Nephritis
    3. Rapidly Progressive Glomerulonephritis
    4. Vasculitis
    5. Curvilinear bodies on electron microscopy

     

  7. What is the most common pulmonary manifestation of SS?
  8.  

    1. Non-specific Interstitial Pneumonia (NSIP)
    2. Lymphocytic Interstitial Pneumonia (LIP)
    3. Usual Interstitial Pneumonia (UIP)
    4. Organizing Pneumonia (OP)
    5. Pulmonary Arterial Hypertension (PAH)

     

  9. You are asked to see a 25 year old woman with sicca, arthritis and Raynaud’s Phenomenon. Her serologic profile is the following: ANA 1:640, positive anti-Ro, positive anti-Smith, positive RF and positive single stranded (ss) DNA. The presence of which auto-antibody suggests more than a diagnosis of SS?
  10.  

    1. ANA
    2. Anti-Ro
    3. Anti-ssDNA
    4. RF
    5. Anti-Smith

     

  11. You are taking care of a 35 year old woman with SS and diabetes mellitus. She complains to you about fatigue and arthralgias. She has trace synovitis in her metacarpal phalangeal joints (MCP) and proximal interphalangeal joints (PIPs). Her sedimentation rate and C-reactive protein are normal. Hand xrays show no erosive changes. She wishes to become pregnant in the near future.What is the best therapy at this time?
    1. Leflunomide
    2. Abatacept
    3. Rituximab
    4. Methotrexate
    5. Hydroxychloroquine

     

  12. You are asked to see a 55 year old woman with a rapidly progressive weakness in her arms and urinary retention. Her physical examination shows upper extremity spasticity and diffusely diminished sensation. Her past medical history is significant for SS, for which she takes cyclosporine eye drops and daily hydroxychloroquine. She recently emigrated from Eastern Europe. What is your next diagnostic test?
  13.  

    1. MRI of the brain
    2. MRI of the thoracic spine
    3. ANA and anti-Ro and anti-La antibodies
    4. Lumbar puncture for oligoclonal bands
    5. PPD

     

Answer Key

  1. The correct answer is A.
  2.  

    The diagnosis of SS rests on objective evidence of serologic, ophthalmologic and oral signs. A recently proposed classification criterion reviewed a range of diagnostic tests and compared them in cases and controls. The combination that yielded the greatest sensitivity and specificity included at least two of the following: 1) Positive serum anti-SSA and/or anti-SSB or (positive RF or ANA titer > 1:320, 2) OSS > 3 or 3) presences of focal lymphocytic sialadenititis with a focus score of > 1. Classification criteria are developed to allow for the enrollment of a standardized group of patients into clinical trials. Elements of the criteria are useful as aids in clinical practice, but may not be applicable in every patient because of practical imitations (a labial salivary gland biopsy may be considered too invasive or may not be feasible). Therefore, the other diagnostic tests listed in the criterion may become valuable substitutes and clinical judgment is still critical.

  3. The correct answer is C.
  4.  

    Patients with SS are at a higher risk for lymphoma with reported odds ratios of up to 40. Risk factors for the development of NHL include the length of time with the disease, low C4, type II cryoglobulins, anemia, lymphocytopenia, hypergammaglobulinemia, cutaneous vasculitis (palpable purpura), lymphadenopathy, splenomegaly, parotid enlargement and peripheral neuropathy. The patient in c has long-standing disease as she is edentulous and has glandular enlargement with palpable purpura, all risk factors for the development of lymphoma. The patients in foil a has mild primary SS and in e has secondary SS, but there is no information given that they have ominous findings for lymphoma. The patient in foil b has sicca from smoking and radiation and in d has sicca from sarcoidosis, hence neither patient is at increased risk for lymphoma associated with SS.

  5. The correct answer is B.
  6.  

    This patient with SS has a distal (type I) renal tubular acidosis (RTA), which is the most common renal manifestation of SS from interstitial nephritis (IN). The pathologic hallmark is infiltration of the interstitium with inflammatory cells (plasma cells, lymphocytes and monocytes), tubular atrophy and fibrosis, resulting in impaired distal acidification. Classic laboratory findings include a hyperchloremic metabolic acidosis with a normal anion gap and hypokalemia. This patient is weak because of the low potassium. RTA is seen early in the disease course and mostly in young patients. It does not evolve into renal failure, but requires lifelong electrolyte replacement, as it is refractory to immunosuppressive therapy in most cases. Although glomerular disease can occur in SS, it is less common than IN, and would have a more active urinary sediment and possible renal compromise. Vasculitis is an uncommon finding in SS. Hydroxychloroquine (HCQ) therapy can cause a neuromyopathy and the classic finding of toxicity is curvilinear bodies on electron microscopy, in any organ. The risk of HCQ toxicity increases with time and dosage. She was recently started on HCQ and would not have had the length of exposure needed to develop this side effect, however vigilance for myopathy is always warranted on this therapy.

  7. The correct answer is A.
  8.  

    SS is a systemic disease and pulmonary involvement is common with an estimated prevalence of significant lung involvement in up to 24% of patients. Pulmonary involvement is associated with a 4-fold increased mortality after 10 years of disease. All of the above lung conditions can be seen in SS, and NSIP is the most common. PAH is seen in other auto-immune diseases, such as the scleroderma spectrum and Mixed Connective Tissue Disease (MCTD), but its occurrence in SS is rare. Pulmonary symptoms in patients with SS should be judiciously evaluated, and when present aggressively treated with a multidisciplinary approach.

  9. The correct answer is E.
  10.  

    It is common to see the following auto-Abs in SS: ANA, Anti-Ro, Anti-La and RF. Anti-ss DNA is not specific. Anti-Smith is specific for lupus and in the setting of arthritis and Raynaud’s Phenomenon, a complete work-up for other auto-immune conditions, including lupus should be pursued.

  11. The correct answer is E.
  12.  

    In this patient with fatigue and inflammatory arthritis, HCQ is the best choice for several reasons:

    1. studies have shown HCQ diminishes the fatigue associated with SS,
    2. HCQ is a good agent for mild inflammatory arthritis,
    3. HCQ may lower serum blood sugar in diabetic patients. In fact, diabetic patients on glucose lowering therapy should be counseled about this effect and medications adjusted accordingly.

      Methotrexate (MTX) and Leflunomide would be reasonable choices for the inflammatory arthritis of SS; however, both are teratogenic and contraindicated in pregnancy. Women should be off of MTX for at least 3 months prior to attempting to conceive. Leflunomide undergoes enterohepatic recirculation and can stay in the system for a long time (up to two years). Blood levels must be tested and negative twice before attempting to conceive for any women who have received leflunomide. Abatacept and Rituximab are two biologic agents which can be used in SS; however, her manifestations are not severe enough at this time to warrant a biologic agent.

  13. The correct answer is B.
  14.  

    This patient has the complication of transverse myelitis from her SS. Transverse myelitis is an inflammatory disorder of the spinal cord that presents with weakness, sensory loss and/or bowel and bladder involvement. In SS, multiple spinal levels are contiguously involved (3 or more levels). This is distinct from multiple sclerosis where multiple non-contiguous levels may be involved. A lumbar puncture is indicated and oligoclonal bands may be positive (1-2 bands) in SS, but it is much lower than the bands seen in MS (2-10 bands). The brain may be involved in SS, but that wouldnot explain her current symptoms. In a patient with known SS, repeating her serologic tests yields no additional information. Finally, she is at risk for TB after living in an endemic area, but she likely has a positive PPD from BCG vaccination.

Last updated February 2015.