Go for the Glory Quiz: Sjögren Syndrome

A 47-year-old woman with a 12-month history of dry mouth and eyes presented with painful bilateral swelling, which was markedly more prominent and painful on the left. She complained of fatigue and polyarthralgias. She was taking levothyroxine for hypothyroidism, and had taken two courses of antibiotics for infection and later prednisone (5-20 mg/day) for the parotid swelling. She denied fevers, weight loss, malaise, and night sweats.

Lab results showed anemia (Hgb 9.8 g/dl), mild thrombocytopenia, positive ANA (1:32), ESR=6-, abnormal salitary scintigraphy, and anti-SSB. A biopsy of the lymph glads showed focal lymphocytic sialadenitis.

• PET/CT of head and neck
• MRI scan of head/neck
• Parotid tail biopsy
• Complement C4/cryoglobulins
• Noncontrast CT of neck

* (Adapted from presentation and responses at a Curbside Consult session during the 2012 annual meeting of the American College of Rheumatology.)

• PET/CT of head and neck (12%)
• MRI scan of head/neck (16%)
• Parotid tail biopsy (32%)
• Complement C4/cryoglobulins (22%)
• Noncontrast CT of neck (18%)

The best choice is noncontrast CT of the neck. These studies ane inexpensive and easy to obtain. They are the best way to look for stones, which are always calcified, and to screen for sialadenosis (fatty infiltration of the glands, which can be due to chronic use of steroids or metabolic problems.

In this case, the CT showed parotid enlargement, but no stones or parenchymal abnormalities. The patient also showed several inflammatory markers (CRP 5 mg/L, increased serum beta2 microglobulin) and low C3 and C4.

Inflammatory sialadenitis is by far the most common cause of intermittent or chronic salivary gland swelling. It is associated with polyclonal B cell activation or elevation of acute phase reactants. The condition is steroid-responsive (e.g. methylprednisolone), but tends to recur when steroids are discontinued. Options for long-term therapy include hydroxychloroquine, methotretaxe, and in the worst cases, IV rituxumab.

This patient was treated with hydroxychloroquine and pilocarpine, but the left parotid gland did not improve. A biopsy of the left parotid tail four months later showed non-Hodgkins B cell lymphoma, which was graded as Stage I and treated with rituximab after referral to oncology. Five years later the patient is doing well.

• Presents at any time
• Often painful
• Unilateral or bilateral
• Intermittent or persistent

Inflammatory sialadenitis
Sialolithiasis (stones)
Sialostenosis (fibrosis of ducts)
Bacterial sialadenitis

Inflammatory sialadenitis
Sialolithiasis
Sialostenosis
Bacterial sialadenitis
Lymphoma

TIPS: SIALOLITHIASIS vs SIALOSTENOSIS

1. Both cause pain and/or swelling after eating.
2. CT is useful for sialolithiasis; less so for sialostenosis
3. Sialolithiasis may cause a sensation of sand or gravel in the mouth.
4. Sialostenosis may leave a sour taste or mucus in the mouth.
5. Both can be treated with secretagogues to stimulate flow or saliva, or by milking (compressing the gland at first sign of pain or swelling). Stones often just pass, but may need to be removed surgically.

• Apply pressure to major salivary gland (or have patient do so). If fluid comes out cloudy or purulent, think infection.
• Usually S. aureus
• Order imaging study to rule out obstruction
• Treatment: Amoxicillin-clavulanate 875 mg bid for 2-4 weeks

Strong association with SjÃ¶gren syndrome (6.6 x relative risk, affects up to 5% of patients within 10 years of disease onset.

Treat aggressively. Tends to recur and mortality rate is high (23-33%, accounting for 20% of deaths among SjÃ¶gren patients).

• Glandular swelling
• Palpable purpura at initial presentation
• Mixed monoclonal cryoglobulinemia
• Low C4

Increasingly Sjogrensyndrome is being recognized in patients who are not Caucasian, the tennis player Venus Williams being a prominent example. We saw a 33-year-old African American woman who experienced severe fatigue eight months after a "viral infection." The problem was so disabling that she was on the point of either losing her job or resigning. After extensive workup by multiple consultants she had been diagnosed with euthyroid Hashimoto's thyroiditis. She had no signs of connective tissue disease other than occasional dry eyes, which could be related to the fact that she wears contact lenses. Her highest recorded TSH measurement was 9mU/L. Treatment with thyroxine failed. The ANA titer was 1:320-640.

Which of the following tests is least helpful for evaluation of fatigue in SjÃ¶gren syndrome?

• Sleep study
• Screening for depression
• Examination of tender points
• Serum vitamin B12
• Empiric treatment with immunosuppressives

* (Adapted from presentation and responses at a Curbside Consult session during the 2012 annual meeting of the American College of Rheumatology.)

• Sleep study (12%)
• Screening for depression (4%)
• Examination of tender points (10%)
• Serum vitamin B12 (10%)
• Empiric treatment with immunosuppressives (65%)

The best choice for the least useful study is examination of tender points, for two reasons: (1) Rarely does diagnosing or treating fibromyalgia in this setting make much difference, and (2) fibromyalgia commonly occurs as a comorbidity of SjÃ¶gren syndrome (SS).

The patient was treated with hydroxychloroquine. Followup after eight months showed that the fatigue and disturbed sleep, as well as myalgias, were resolved. She was able to keep her job.

1. Fatigue can be an isolated presenting symptom in SS.
2. It is one of the most common and disabling symptoms of SS, with a severe impact on quality of life.
3. There are multiple causes.
4. It is challenging to treat, but not impossible.

DIFFERENTIAL DIAGNOSIS

Systemic inflammation
Disturbed sleep
Anxiety and depression
Fibromyalgia
Hypothyroidism
Medication side effects
Vitamin D deficiency
Vitamin B12 deficiency
Muscle inflammation
Associated celiac disease
Infection.

1. Start hydroxychloroquine
2. For treatment failures consider other symptoms such as polyarthralgias. Add second line agent after several months if appropriate (e.g. methotrexate).
3. When in doubt, prescribe prednisone 15 mg daily for 2 weeks followed by rapid taper. If condition truly is inflammatory fatigue will resolve within 1-2 days, invariably followed by a flare at taper.
4. If you see a response to steroids, start a second line agent (methotrexate or azathioprine) or in the worst case consider IV rituximab.¹
5. Treat nocturnal dryness with ocular gels; coat tongue with vitamin E oil or moisturizing gels. Recommend a humidifier at night and secretagogues at bedtime.
6. Prescribe sleep medications, but beware of the risk of increasing dryness.
7. When in doubt, order a sleep study.

A 65-year-old woman with biopsy-proven primary SS returned after a long hiatus with a five-month history of numbness, tingling, burning, and "creepy crawly" sensations, mostly in her extremities but sometimes affecting her trunk or scalp. The symptoms had progressed to the point where they were interfering with ambulation. She also reported memory loss and poor concnetration. Physical examination revealed dry mouth, absent ankle jerks (not unexpected in a woman of that age group), and right ankle dorsiflexor weakness. Sensory testing was equivocal and muscle enzymes were normal.

You suspect peripheral neuropathy. Which test are you least likely to order?

• Sural nerve and calf muscle biopsy
• Quantitative sensory testing
• Neurologic consultation for EMG/nerve conduction study of the lower extremities
• Cutaneous biopsy for epidermal nerve fiber density
• Serum Vitamin B12

* (Adapted from presentation and responses at a Curbside Consult session during the 2012 annual meeting of the American College of Rheumatology.)

• Sural nerve and calf muscle biopsy (22%)
• Quantitative sensory testing (13%)
• Neurologic consultation for EMG/nerve conduction study of the lower extremities (11%)
• Cutaneous biopsy for epidermal nerve fiber density (47%)
• Serum vitamin B12 (8%)

The test least likely to be useful is quantitative sensory testing. It is difficult to obtain, operator-dependent, and often does not provide much information.

The first test to choose is EMG, to determine whether motor nerves are involved. If the EMG result is negative, a followup test would be skin biopsy for nerve fiber density testing, to assess for small fiber neuropathy. In most cases the consulting neurologist will follow up with tests for further causes.

Although this patient showed dermatographism indicative of a sensitivity to food dyes which may cause chronic itching, asymmetric sensorimotor neuropathy was diagnosed based on EMG. Followup with a sural nerve calf muscle biopsy demonstrated vasculitis, demyelination, and axonal degeneration, which were treated with azathioprine. Because of the patient's concern about memory loss, she was also referred for neuropsychiatric testing, which revealed no significant problems other than anxiety. As in many cases of SS, the patient's level of distress about this concern was out of proportion with the symptoms demonstrable on objective testing.

• A caveat: Confusingly in this context, patients with SS have a predisposition to urticaria and chronic itching which can be easily discerned if they show dermatographism. Often this is due to a sensitivity to tartrazine, which can be resolved with antihistamines and a tartrazine-free diet.

• The most common cause of peripheral neuropathy in SS is distal sensory neuropathy. This is a diagnosis of exclusion. The course is highly variable.

• Small fiber neuropathy typically involves small fiber unmyelinated cutaneous nerves, diagnosed by skin biopsy for epidermal nerve fiber density when EMG and nerve conduction studies are normal. Treatment is symptomatic (e.g. gabapentin); course is variable.

• Nerve biopsy is in order when (1) there is rapid onset and progression, with (2) an asymmetric mononeuropathy/multiplex pattern on EMG.

• There are no randomized trials to guide treatment. Options (with the decision based on severity, progression, and involvement of other organs) range from no treatment or symptomatic therapy to intravenous IG, azathioprine, oral or IV cyclophosphamide, or IV rituximab.

Go for the Glory Quiz: Sjögren Syndrome

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