BASICSMariya Milko, DO, MS • Rubaiya Mallay, DO, FACOI, ACR
BASICS
• Chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs
• Typically presents with diminished salivary and lacrimal gland function, resulting in sicca symptoms such as dry eyes (xerophthalmia), dry mouth (xerostomia), and parotid enlargement
• Extraglandular manifestations: arthralgia, myalgia, Raynaud phenomenon, pulmonary disease, GI disease, leukopenia, anemia, lymphadenopathy, vasculitis, renal tubular acidosis, lymphoma, CNS involvement with longitudinal transverse myelitis (>4 vertebral segments), and optic neuritis associated with anti-aquaporin-4 antibodies, PNS involvement with small fiber neuropathy
• Primary Sjögren: Not associated with other diseases; HLA-DRB1*0301 and HLA-DRB1*1501 are the most common.
• Secondary Sjögren: complication of other rheumatologic conditions, most commonly rheumatoid arthritis; associated with HLA-DR4
• First described by Swedish ophthalmologist Henrik Sjögren (1899–1986)
EPIDEMIOLOGY
Incidence
Annual incidence: ~4/100,000. Primary SS is one of the most common autoimmune diseases, affecting 1–4% of population.
• All races are affected
• Predominant sex: female > male (9:1)
• Predominant age: can affect patients of any age but is most common in the elderly; onset typically in the 4th to 5th decades of life
Prevalence
Sjögren syndrome (SS) affects 1 to 4 million people in the United States.
ETIOLOGY AND PATHOPHYSIOLOGY
• Multifactorial systemic autoimmune process characterized by infiltration of glandular tissue by CD4 T-lymphocytes
• Theorized that glandular epithelial cells present antigen to the T cells. Cytokine production then occurs. There is also evidence for B-cell activation, resulting in autoantibody production and an increased incidence of B-cell malignancies.
• Etiology is unknown. Estrogen may play a role because SS is more common in women. Exogenous factors such as viral proteins (EBV, HCV, HTLV-1) have also been implicated.
Genetics
• A familial tendency suggests a genetic predisposition.
• Associations in the HLA regions HLA-DQA1*0501, HLA-DQB1*0201, and HLA-DRB*0301 are the strongest genetic risk factors for SS.
RISK FACTORS
There are no known modifiable risk factors.
GENERAL PREVENTION
• No known prevention. Complications can be prevented by early diagnosis and treatment.
• Oral health providers play a key role in early detection and management of symptoms resulting from salivary dysfunction (1)[C].
COMMONLY ASSOCIATED CONDITIONS
Secondary SS associated with rheumatoid arthritis, scleroderma, systemic lupus erythematosus (SLE), polymyositis, HIV, hepatitis C, MCTD, PBC, hypergammaglobulinemic purpura, necrotizing vasculitis, autoimmune thyroiditis, chronic active hepatitis, mixed cryoglobulinemia
Pregnancy Considerations
Pregnant SS patients with anti-SSA Abs have increased risk of delivering fetus with skin rash and 3rd-degree heart block.
DIAGNOSIS
• American College of Rheumatology Diagnostic Criteria (2)[A]: Individuals with signs/symptoms that may be suggestive of SS, who have at least two of the following three objective features:
– Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and ANA titer—1:320)
– Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score 1 focus/4 mm2
– Keratoconjunctivitis sicca with ocular staining score >3 (assuming that individual is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years)
• Ocular signs and symptoms
– Troublesome dry eyes daily for >3 months
– Recurrent sandy/gritty ocular sensation
– Use of tear substitute >3 times per day
• Oral signs and symptoms
– Daily symptoms of dry mouth for ≥3 months
– Recurrent feeling of swollen salivary glands
– Need to drink liquid to help swallow dry foods
• Other manifestations: chronic arthritis, type 1 RTA, tubular interstitial nephritis, rheumatoid arthritis, vasculitis, vaginal dryness, pleuritis, pancreatitis
HISTORY
• Decreased tear production; burning, scratchy sensation in eyes
• Difficulty speaking/swallowing, dental caries, xerotrachea
• Enlarged parotid glands or intermittent swelling (bilateral)
• Dyspareunia; vaginal dryness
PHYSICAL EXAM
Common physical exam findings include:
• Eye exam: dry eyes (keratoconjunctivitis sicca), decreased tear pool in the lower conjunctiva, dilated conjunctival vessels, mucinous threads, and filamentary keratosis (slit-lamp examination)
• Mouth exam: dry mouth (xerostomia); decreased sublingual salivary pool (tongue may stick to the tongue depressor); frequent oral caries (sometimes in unusual locations such as the incisor surface and along the gum line); dark red tongue from prolonged xerostomia
• Ear, nose, and throat exam: parotid enlargement, submandibular enlargement
• Skin exam: nonpalpable or palpable vasculitic purpura (typically 2 to 3 mm in diameter and on the lower extremities)
DIFFERENTIAL DIAGNOSIS
• Causes of ocular dryness: hypovitaminosis A, decreased tear production unrelated to autoimmune process, chronic blepharitis or conjunctivitis, impaired blinking (i.e., due to Parkinson disease or Bell palsy), infiltration of lacrimal glands (i.e., amyloidosis, lymphoma, sarcoidosis), low estrogen levels
• Causes of oral dryness: anticholinergic medications, sialadenitis due to chronic obstruction, chronic viral infections (i.e., hepatitis C or HIV), radiation of head/neck
• Causes of salivary gland swelling: unilateral: obstruction, chronic sialadenitis, bacterial infection, neoplasm; bilateral (asymmetric): IgG4-related disease, HIV bilateral (symmetric): hepatic cirrhosis, DM, anorexia/bulimia, acromegaly, alcoholism, hypolipoproteinemia, chronic pancreatitis, acute or chronic viral infection (i.e., mumps, Epstein-Barr virus [EBV], coxsackievirus, echovirus, granulomatous diseases (i.e., tuberculosis, sarcoidosis)
DIAGNOSTIC TESTS & INTERPRETATION
The following tests can be used to support diagnosis:
• Schirmer test (<5-mm wetness after 5 minutes)
• Rose Bengal test (slit lamp)
• Minor salivary gland biopsy (gold standard)
• Auto antibodies: +ANAs (95%), +RF (75%)
• In primary SS: +anti-Ro (anti-SSA, 56%) and +anti-La (anti-SSB, 30%)
Initial Tests (lab, imaging)
Preliminary lab workup
• Basic labs: CBC with differential, BUN/creatinine (Cr), AST/ALT, ESR, C-reactive protein (CRP), urinalysis (UA)
• Special labs: ANA, rheumatoid factor (RF), anti-Ro/SSA, anti-La/SSB, ESR, CRP
• Anti-SSA and anti-SSB antibodies present in 33–74% and 23–52% of SS patients, respectively.
• Other auto antibodies-muscarinic receptor type 3 (M3R) and anti-α-fodrin are being explored with good specificity (3)[A].
• Initial imaging studies may include:
– Imaging for xerostomia: salivary gland scintigraphy (insensitive but highly specific)
– Parotid gland sialography (should not be used in acute parotitis)
– MRI (correlates well with salivary gland biopsy)
• A novel diagnostic tool is Salivary Gland US (SGUS) which is noninvasive and highly specific for salivary gland involvement in SS (4)[A].
• Salivary gland biopsy: used to confirm suspected diagnosis of SS or to exclude other causes of xerostomia and bilateral glandular enlargement
• Parotid biopsy if malignancy is suspected
• Lymph node biopsy to rule out pseudolymphoma or lymphoma if suspected
Test Interpretation
• Salivary gland histology shows focal collections of lymphocytes; immunocytology shows CD4+ T cell lymphocyte predominance.
• SGUS parameters include:
– Parenchymal nonhomogeneity—the most useful diagnostic marker with high specificity and good sensitivity (4)[A].
– US inflammatory findings include hypoechoic and hyperechoic bands (4)[A].
– Real-time sonoelastography (RTS) to quantify tissue rigidity and assess glandular damage (4)[A]
TREATMENT
• Treatment is primarily supportive.
• Treat sicca symptoms—dry eyes, dry mouth
• Avoid medications that may worsen oral dryness (i.e., anticholinergics).
• Promote good oral hygiene.
• Treat systemic manifestations.
• Address fatigue and pain.
MEDICATION
• Therapy for sicca symptoms: artificial tears and ocular lubricants (5)[C]
• Topical therapy for dry mouth: can be as simple as liberally drinking sips of water, trying sugar-free lemon drops or artificial saliva preparations such as Salivart, Saliment, Xero-Lube, MouthKote
• Immunosuppressive therapy such as hydroxychloroquine can be used for systemic symptoms; however, it has not shown any benefit in relieving refractory sicca symptoms.
• Evoxac (Cevimeline) may be prescribed for SS-associated xerostomia. It works by stimulating muscarinic cholinergic receptors to increase salivary gland secretion.
• Dry eyes are graded by severity of symptoms, conjunctival injection and staining, corneal damage, tear quality, and lid involvement. Artificial tears may be used; however, artificial tears with hydroxyethylcellulose or dextran are more viscous and can last longer.
• Acetaminophen or NSAIDs for arthralgias
First Line
• Xerostomia: sugar-free lozenges, especially malic acid, artificial saliva; pilocarpine 5 mg PO QID or cevimeline 30 mg PO TID
• Keratoconjunctivitis sicca: artificial tears and ocular lubricants for symptomatic relief, topical cyclosporine (Restasis), or autologous tears
Second Line
• Xerostomia: Interferon-alfa lozenges may enhance salivary gland flow.
• Keratoconjunctivitis sicca: topical glucocorticoids or topical NSAIDs (use with caution)
• Immunosuppressive therapy: antimalarials (e.g., hydroxychloroquine) for arthralgias, lymphadenopathies, and skin manifestations; may then consider methotrexate or cyclosporine, which showed subjective improvement but no significant objective improvement
• Early studies show improvement in fatigue with rituximab (6)[B].
• For life-threatening extraglandular manifestations, cyclophosphamide (PO or IV), mycophenolate mofetil, and azathioprine are often used.
ISSUES FOR REFERRAL
• A rheumatologist can help with management of systemic manifestations or resistant symptoms.
• Oral health
• Ophthalmology, for grading of severity and management of xerophthalmia
ADDITIONAL THERAPIES
• Patients should use vaginal lubricants, such as Replens, for vaginal dryness. Vaginal estrogen creams can help in postmenopausal women. Be alert for and treat vaginal yeast infections.
• Xerostomia: small sips of water, good dental care
• Keratoconjunctivitis sicca: Conserve tears with side shields or ski/swim goggles, humidifiers, and moist washcloths.
• Dehydroepiandrosterone (DHEA) does not offer improvement in fatigue and well-being above placebo.
SURGERY/OTHER PROCEDURES
Keratoconjunctivitis sicca: If refractory to artificial tears, punctal occlusion is the treatment of choice.
COMPLEMENTARY & ALTERNATIVE MEDICINE
• Some studies show acupuncture benefits saliva production and symptoms of xerostomia.
• There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms or saliva production in patients with Sjögren syndrome.
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
May be required for extraglandular manifestations, such as cardiopulmonary disease, renal involvement, and CNS manifestations (e.g., optic neuritis, transverse myelitis, vasculitis, or ischemic stroke)
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Frequency of follow-up depends on severity
Patient Monitoring
• Monitor for complications, systemic manifestations, and relief of symptoms.
• Medicolegal pitfalls: Monitor for parotid tumor or lymphoma.
PATIENT EDUCATION
In most cases, simple measures are adequate: humidifiers, sips of water, chewing gum, or artificial tears.
PROGNOSIS
• Hypocomplementemia is an independent risk factor for premature death.
• Primary SS is associated with increased risks of malignancy, non-Hodgkin lymphoma, and thyroid cancer.
COMPLICATIONS
Complications include dental caries, gum disease, dysphagia, salivary gland calculi, keratitis, conjunctivitis, and scarring of the ocular surface.
REFERENCES
1. Mays JW, Sarmadi M, Moutsopoulos NM. Oral manifestations of systemic autoimmune and inflammatory diseases: diagnosis and clinical management. J Evid Based Dent Pract. 2012;12(3 Suppl):265–282.
2. Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken). 2012;64(4):475–487.
3. Deng C, Hu C, Chen S, et al. Meta-analysis of anti-muscarinic receptor type 3 antibodies for the diagnosis of Sjögren syndrome. PLoS One. 2015;10(1):e0116744.
4. Luciano N, Valentini V, Calabrò A, et al. One year in review 2015: Sjögren’s syndrome. Clin Exp Rheumatol. 2015;33(2): 259–271.
5. Aragona P, Spinella R, Rania L, et al. Safety and efficacy of 0.1% clobetasone butyrate eyedrops in the treatment of dry eye in Sjögren syndrome. Eur J Ophthalmol. 2013;23(3):368–376.
6. Meijer JM, Meiners PM, Vissink A, et al. Effectiveness of rituximab treatment in primary Sjögren’s syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(4):960–968.
CODES
ICD10
• M35.00 Sicca syndrome, unspecified
• M35.02 Sicca syndrome with lung involvement
• M35.09 Sicca syndrome with other organ involvement
CLINICAL PEARLS
• Many symptoms of SS can be treated with simple interventions such as artificial tears and sugar-free lozenges.
• Consider lacrimal duct plugs for dry eyes.
• Consider SS in patients with unexplained lung disease and +ANA.
• Patients with primary SS may have an increased incidence of celiac disease because both disease share similar genetics.