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Contributor: Amy C. Cannella, MD
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.
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.
(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom of this page.)
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
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.
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.
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.
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.
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.
In this patient with fatigue and inflammatory arthritis, HCQ is the best choice for several reasons:
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.
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.