BOTTOM LINE

SjD is an autoimmune systemic rheumatic disease characterized by lacrimal and salivary gland inflammation/dysfunction, most often presenting in females in their 30-50s. Systemic features include parotid gland enlargement, inflammatory arthritis, cytopenias, hypergammaglobulinemia, gastroparesis, renal failure, ILD, or small fiber neuropathy. Evidence of autoimmunity often manifests as either a positive anti-SSA/Ro, or a high-titre ANA combined with positive RF; diagnosis should not be made solely on the basis of a positive anti-SSA/Ro. Objective findings of ocular/oral dryness may support diagnosis and include: lip biopsy, evidence of dry eye (Schirmer’s test or abnormal ocular staining), or evidence of salivary gland involvement (salivary flow rate, salivary scintigraphy, salivary gland ultrasound or CT/MRI). Treatment of sicca symptoms is supportive, and does not change regardless of an SjD diagnosis. Systemic features may require immunosuppressive medications, but evidence is minimal.
[🕑 14 minute read]

EPIDEMIOLOGY

• Incidence, prevalence
  • Reported incidence and prevalence varies widely in literature due to different classification criteria and methods
  • Annual Incidence: 0.3-26/100,000 
  • Pooled prevalence: 60.8/100,000
• Age, Sex
  • Age: onset 34-57 years-old
  • Sex: Female >> Male, 14:1
  • Men may present with more severe ocular disease and less systemic and immunological involvement vs. women

• Ethnicity
  • Age at diagnosis
    • African patients are diagnosed mean 7-years earlier than caucasian patients
  • Female:male ratio
    • Asian patients have highest female to male ratio (27:1)
    • African patiensts have lowest female to male ratio (7:1)
  • Prevalence
    • 2-3 times higher prevalence reported in African-American patients vs. Caucasian patients.
• Risk factors
  • Genetic
    • HLA Class II associated: HLA-DQB1, HLA-DQA1
    • Non-HLA: IRF5, STAT4, BLK, IL-12A, TNIP1, and CXCR5
    • Epigenetic: includes DNA hypomethylation, histone acetylation and microRNA expression
  • Environmental
    • Viral infection (ex: EBV, HHV6, HTLV1, Hepatitis C)

CLINICAL MANIFESTATIONS

—PHENOTYPES

BALS: B cell active, low symptoms

• Characteristics
  • Younger, ↓symptom burden, ↓systemic disease
  • ↑B-cell activity (↑IgG, RF+, ↓C4, ↑frequency anti-SSA and anti-SSB)
• Lymphoma risk
  • Intermediate
• High IFN Signature
  • More frequent
  • High IFN signature in BALS predicts lymphoma and disease progression

HSA: High systemic activity

• Characteristics
  • ↑Male, ↑dryness/fatigue, ↓pain,
  • ↑systemic activity (ex: lymphadenopathy, skin, lung, peripheral nervous system involvement)
  • ↑frequency antibodies other than anti-SSA or anti-SSB (anti-RNP, anti-centromere) and cryoglobulinemia.
• Lymphoma risk
  • Higher
• High IFN Signature
  • Intermediate frequency

LSAHS: Low systemic activity., high symptom burden

• Characteristics
  • ↑Reported symptom burden
  • ↓ low systemic disease activity
• Lymphoma risk
  • Low
• High IFN Signature
  • Lower frequency

Several other similar phenotypes described in literature

—GLANDULAR MANIFESTATIONS

OCULAR

• Dry eye
  • Keratoconjunctivitis sicca
  • Onset can vary widely; can be ~10 years before SjD diagnosis
  • Insidiously worsening gritty/sandy sensation with itching, photophobia, visual blurring
  • Vision-threatening disease may occur, can be associated with severe systemic extra-glandular Sjogren’s features (ex: peripheral neuropathy, interstitial nephritis, vasculitis)
  • May develop corneal ulceration, perforation, melt

ORAL

• Dry mouth (xerostomia) complications
  • Mucosal
    Mouth sores, glossodynia, stomatopyrosis, dysgeusia, cheilosis, hoarseness/dysphonia
  • Dental
    Cavities, cracked teeth, poor restorative dental work outcomes
  • Candida
    Chronic candidal overgrowth causing stomatopyrosis, spice/acid intolerance, tongue erythema
  • Glandular
    Acute, intermittent, or chronic uni/bilateral swelling of parotid or submandibular glands (30%)

Increased risk of non-Hodgkin’s lymphoma in patients with chronic parotid gland swelling

OTHER SICCA

• Xeroderma, chronic pruritus, xeromycteria, epistaxis, dry pruritic ears
• Xerotrachea, cough, vaginitis sicca and dyspareunia
  • Consider secondary causes of sicca, including: anticholinergic drugs, head/neck radiation therapy,  Hepatitis C, HIV, pre-existing lymphoma, sarcoidosis, graft-versus-host disease

 Note: dry eyes and mouth are common; prevalence of dry eyes/mouth increases with age
<5% prevalence before age 40; ~10% increase in prevalence per decade after age 60

—EXTRA-GLANDULAR MANIFESTATIONS

• SYSTEMIC
  • Fatigue (70-80%), fevers (6-13%), weight loss, lymphadenopathy
• MSK
  • Arthralgias (50-75%)
  • Inflammatory arthritis — usually rheumatoid pattern but non-erosive (10-30%); can also be non-rheumatoid (ex: oligoarticular or asymmetrical)
  • Myalgias 70%, inflammatory myositis <2%, inclusion body myositis <1%
• HEMATOLOGICAL
  • Hemoglobin
    • Anemia of chronic inflammation (15-45%)
    • Rare reported hemolytic/aplastic/pernicious anemia, myelodysplastic syndrome, pure red cell aplasia
  • Leukocytes
    • Neutropenia (10-25%), may be associated with development of lymphoma
    • Can be due to drug effect or disease
  • Platelets
    • Thrombocytopenia (5-13%)
  • Hypergammaglobulinemia
    • Hypergammaglobulinemia (20-30%)
    • Related to lymphocytic infiltration of organs, polyclonal B-cell hyperactivity
    • Also: hypo-gammaglobulinemia (5-15%)
  • Monoclonal gammopathy
    • Monoclonal gammopathy 5-10%
    • IgG > IgM isotype; IgA and free light chains reported. Many are cryoglobulins
    • Monoclonal immunoglobulins associated with pulmonary manifestations, hematologic malignancy
  • Cryoglobulins
    • Cryoglobulins, 10-20%; most frequently Type II (monoclonal IgM, polyclonal IgG)
    • Marker of systemic involvement and poor prognostic indicator
  • Associated with lymphoma, cutaneous vasculitis, hypocomplementemia, glomerulonephritis
  • Lymphoproliferative disease
    • See “Associated Disorders” below
• GASTROINTESTINAL
  • Esophageal
    • Dysphagia, GERD:
      Related to diminished saliva, dysmotility, delayed gastric emptying time
  • Gastric
    • Gastroparesis
    • Nausea, dyspepsia, epigastric pain
    • Chronic atrophic gastritis
  • Intestinal
    • Constipation:
      Lack of saliva flow or dysmotility
    • Diarrhea:
      From comorbid Celiac, secretagogues, pancreatic disease, lozenges containing xylitol/sorbitol
    • GI vasculitis
      Rare but reported, presenting as acute abdominal pain, bleeding, perforation or infarction
  • Pancreatic
    • Pancreatic exocrine insufficiency, 36-63%
    • Non-autoimmune chronic pancreatitis <2-5%, acute pancreatitis rare but reported
    • Autoimmune pancreatitis: rare but reported.
  • Hepatobiliary
    • Elevated liver enzymes, 10-40%
      • Drug toxicity
      • Comorbid PBC, PSC, autoimmune hepatitis
      • Rule out hepatitis C infection
• RENAL
  Clinically overt renal disease, 5-10%
  Onset around the time of SjD diagnosis; ~10% may occur 5 or more years later
  ~5-10% progress to end-stage kidney disease
  
  • Tubulo-interstitial Nephritis (TIN)
    • 98% of biopsy-proven renal SjD, 75% occurring in isolation without GN
    • Presentation: Typically subtle minimal creatinine elevation, proteinuria, and electrolyte disturbances
    • Chronic TIN presents with chronic kidney disease and often renal tubular acidosis
    • Consider differential etiology of IgG4-RD, sarcoidosis, infection, drug toxicity, lymphoma, leukemia
  • RTA Type 1: Most common manifestation of renal Sjogren’s
    • Distal renal tubular acidosis (RTA type 1), ~10-40%
    • Alpha-intercalated cells of the collecting duct fail to secrete hydrogen ions into urine
    • Failure to acidify urine leads to hypokalemia (muscle cramps, periodic paralysis, cardiac dysrhythmias) and potential nephrocalcinosis/-lithiasis due to calcium phosphate precipitation
  • RTA Type 2
    • Proximal renal tubular acidosis (RTA type 2), <3% (rare)
    • Proximal tubule fails to reabsorb bicarbonate; may lead to osteomalacia, nephrolithiasis/calcinosis
  • Diabetes Insipidus
    • Nephrogenic diabetes insipidus
    • Can lead to polyuria, nocturia, polydipsia
  • Glomerulonephritis: usually in association with cyroglobulinemia
    • Glomerulonephritis, rare: ~2% of renal biopsies; often found with concurrent TIN
    • Most commonly membranoproliferative GN
    • Associated with non-Hodgkin lymphoma and mortality
• RESPIRATORY
  Clinically significant pulmonary disease, 10-20%
  
  • Interstitial Lung Disease (ILD)
    • Prevalence 3-11%
    • Onset: may precedes SjD diagnosis, onset concurrently at diagnosis, or following diagnosis
    • Risk factors: older age, Raynaud’s, esophageal involvement, smoking, anti-SSA/Ro antibodoies
    • PFTs: restrictive physiology with decreased DLCO
    • CT patterns: NSIP (30%), UIP (25%), LIP (10%), OP (10%)
  • Other
    • Recurrent infectious pneumonia (10-20%)
    • Chronic cough (60%)
    • Xerotrachea
    • Pleural effusions/pleuritis (rare)
• DERMATOLOGIC
  • Xerosis (dry skin), 50%
  • Cutaneous vasculitis: leukocytoclastic vasculitis ± cryoglobulins, urticarial vasculitis; indicator of poorer prognosis
  • Annular erythema, resembling subacute cutaneous lupus erythematosus
  • Raynaud’s
  • Other: cutaneous amyloid, vitiligo, alopecia, neutrophilic dermatoses, lichen planus, granulomatous panniculitis, erythema elevatum diutinum, erythema multiforme-like, erythema nodosum-like
• NEUROLOGIC
  • Peripheral Nervous System
    • Most common: axonal sensory polyneuropathies and small fiber sensory neuropathy (20-30%)
    • Other patterns: sensory ganglionopathy, cranial neuropathy (16-20%), mononeuritis multiplex (12%)radiculoneuropathy, autonomic neuropathy, CIDP
  • Central Nervous System
    • Demyelinating CNS lesions in brain and spinal cord mimicking multiple sclerosis (MS)
      • Can manifest optic neuritis, paresis, ataxia, sphincter dysfunction, cognitive dysfunction, paresthesias. Rare.
      • Could distinguish from MS: lack of oligoclonal banding on CSF, longitudinally extensive transverse myelitis, white matter lesions that spare corpus callosum. N.B.: white matter lesions are nonspecific
    • Recurrent aseptic meningitis
    • Neuromyelitis optica (NMO):
      • Optic neuritis, longitudinally extensive transverse myelitis, anti-aquaporin-4 (NMO-IgG) antibodies
  • Autonomic
    • Prevalence 3-50%, depending on definition and assessment
    • Persistent tachycardia, orthostatic hypotension, GI dysmotility, bladder dysfunction, hypo/anhidrosis
  • Cognitive
    • “Brain fog”, mild cognitive impairment, dementia

—ASSOCIATED DISORDERS

• LYMPHOMA
  • Prevalence of lymphoma following SjD diagnosis
    • 5 years: 5%
    • 15 years: 10-15%
    • 20 years: 18-20%
  • Risk of non-Hodgkin lymphoma (NHL):
    • 15-20x higher than general population
  • Risk factors for lymphoma:
    • Salivary gland enlargement (more often unilateral and persistent in NHL vs. bilateral and intermittent from SjD)
    • Palpable purpura, lymphadenopathy, splenomegaly
    • Low complement C4
    • Cryoglobulinemia
    • Lymphopenia
    • RF positivity
    • High ESSDAI score (indicating higher disease activity)
  • Type of lymphoma
    • Most common: low-grade B-cell non-Hodgkin lymphoma of the marginal zone histologic type, especially MALT lymphoma
    • Other reported types: lymphoplasmacytoid lymphoma, diffuse large-B-cell lymphoma
  • Prognosis of NHL in SjD typically good (especially MALT subtype):
    • 3-year survival 97%, event-free survival of 78%
• OVERLAP SYSTEMIC RHEUMATIC DISEASE
  Prevalence in SjD:
  • SLE: 10-15%
  • RA: 7– 17%
  • SSc: 5-10%
• OTHER
  • Fibromyalgia ~10-30%

INVESTIGATIONS

—BASIC BLOODWORK

• CBC
  • CBC with differential and smear: screen for cytopenias and dysplastic cells
  • Flow cytometry: not standard for initial screening; as indicated
• Electrolytes
  • Consider to screen for hypokalemia and low serum bicarbonate due to RTA type 1
• ALT, ALP
  • Consider to screen for comorbid AIH, PBC, PSC, Hepatitis C; in case of possible future drug exposure
• CK
  • Consider to screen for myositis, depending on clinical suspicion
• Creatinine, urinalysis
  • Creatinine, urinalysis, urine ACR or PCR for renal involvement
• ESR, CRP
  • ESR elevated 20%; related to underlying hypergammaglobulinemia
  • CRP usually normal
• C3, C4
  • Low C3 (10-15%), Low C4 (5-20%)
  • May reflect disease activity due to complement consumption from immune complex formation
• Cryoglobulins
  • Circulating cryoglobulins, usually Type II (monoclonal IgM, polyclonal IgG), 10-20%
• SPEP, quantitative immunoglobulins
  • Polyclonal hypergammaglobulinaemia due to polyclonal B-cell activation
  • Monoclonal gammopathy of undetermined significance (MGUS) up to 20%
    • MGUS has higher prevalence in patients with parotid gland and extra-glandular features of SjD
    • MGUS associated with poorer prognosis
• Infections
  • Causes of secondary sicca: hepatitis C, hepatitis B, HIV

—SEROLOGY

Obtain ANA, ENA, and RF; further serology based on clinical suspicion

• ANA
  • ANA by immunofluorescence, positive >80%
• ENA
  • Anti-Ro/SSA+ 70%
  • Anti-La/SSB+ on 50%
  • Isolated anti-La/SSB positivity without concomitant anti-Ro/SSA positivity is rare in Sjogren’s and of uncertain significance.
• RF, ACPA
  • Rheumatoid factor positive in ~60-70%
  • Anti-citrullinated protein antibody ~5-10%
• Anti-phospholipid antibodies
  • Anti-phospholipid antibodies 13-38%
  • Low titre without thrombosis or recurrent fetal loss; may simply be epi-phenomenon of polyclonal B cell activation
• AMA, ASMA
  • AMA (Anti-mitochondrial antibody) ~2-8%: consider ordering if clinical features of PBC (elevated ALT, ALP)
  • ASMA (Anti-smooth muscle antibody): consider ordering if unexplained elevation in ALT
• Before pregnancy
  • Anti-SSA/Ro
  • Anticardiolipin, anti-beta 2 glycoprotein
  • Lupus anticoagulant

—OTHER TESTING

Consider if confirmation of SjD diagnosis is felt to be required, based on suspicion

• SALIVARY GLAND TESTING
  • Salivary flow
    • Measure patient salivary expectorant over 5 minutes, divide by the collection time.
    •  ≤0.1mL/min of saliva expectorant meets inclusion for the 2016 ACR-EULAR classification for SjD
  • Salivary gland biopsy
    • Could consider if confirmation of diagnosis is felt to be necessary and anti-Ro/SSA antibody negative
    • Technique: linear incision of the buccal side of the lower lip to obtain 3-6 glands
      • Biopsy should be performed by an experienced clinician to minimize complications and ensure adequate tissue sampling
    • Findings:
      • Focal lymphocytic sialadenitis (≥50 mononuclear cells in periductal/periacinal distribution), 82.4% sensitivity and 82.6% specificity
      • Focus score = [(number of foci) / (total surface area of normal appearing tissue)]*4
      • Focus score ≥1/4 mm² of glandular tissue consistent with the salivary component of SjD
  • Salivary gland ultrasonography
    • Findings: heterogeneous parenchyma (hypo/anechoic areas ± hyperechoic bands), intra-glandular calcifications, enlarged lymph nodes, poor visualization of posterior glandular border
    • Hyperechoic bands may be seen in normal people due to aging
    • Hocevar scoring system is commonly used to standardize the assessment of salivary gland ultrasonography
    • Specificity 81-99%, Sensitivity 48-91%
    • Limited by variable sonographer experience, equipment, technique
  • Scintigraphy
    • IV administration of Tc-99m pertechnetate, then patient scanned for 60 minutes
    • Uptake of isotope within 30 minutes followed by excretion; lemon drops given in last 15 minutes 
    • Reveals 3 phases of salivary gland function: uptake, secretion, and stimulated function
    • Defect in ≥ 1 of 3 phases of salivary gland function supportive of SjD
  • MRI, CT
    • MRI: glandular edema → glandular cysts, fatty change → glandular atrophy
    • CT: glandular enlargement, nodularity, cystic or fatty change, atrophy
    • MRI and CT are typically reserved for cases where there is a suspicion of malignancy or other structural abnormalities not detected by ultrasound (in centres with reliable sonography)
• OCULAR TESTING
  • Schirmer’s Test
    • Normal: ≥10mm wetting of test strip over 5 minutes
    • Suggests SjD: ≤5mm wetting of test strip over 5 minutes
  • Staining
    • Fluorescein with lissamine green staining reveals corneal and/or conjunctival epithelial damage
    • Ocular Surface Staining Score ≥5 on a 0-12 scale considered clinically significant
  • Ocular Surface Disease Index (OSDI):
    • Questionnaire assessing the severity of dry eye symptoms; often used in conjunction with Schirmer’s test and staining

DISEASE MEASURES

ESSDAI: EULAR Sjögren’s syndrome disease activity index

• Mostly for research purposes; measures disease activity in primary SjD
• Assesses disease activity in 12 domains:
• Constitutional
• Lymphadenopathy
• Glandular
• Articular
• Cutaneous
• Pulmonary
• Renal
• Muscular
• Peripheral nervous system
• Central nervous system
• Hematological
• Biological

ESSPRI: EULAR Sjogrenb’s Syndrome Patient Reported Index

• Evaluates patient-reported symptoms such as dryness, pain, and fatigue

DIAGNOSIS

Primary SjD should be suspected in patients, usually females in their 30-50s presenting with compatible symptoms of sicca and/or extra-glandular involvement, evidence of autoimmunity, and objective evidence of glandular dysfunction. Sicca symptoms include ocular and/or oral dryness requiring topical lubricating eye drops and possibly care for recurrent dental caries. Systemic features may include parotid gland enlargement, cytopenias, hypergammaglobulinemia, MGUS, inflammatory arthritis, gastroparesis, renal failure, ILD, or small fiber neuropathy.  Evidence of autoimmunity should often present: either a positive anti-SSA/Ro, or a high-titre ANA combined with positive RF; diagnosis should not be made solely on the basis of a positive anti-SSA/Ro, since this antibody can be found in other diseases and in healthy people. Occasionally, patients might present with minimal sicca but have compatible systemic features and evidence of autoimmunity. If confirmation of SjD is required, especially if the serology is negative, then multiple objective findings of ocular/oral dryness should be sought: a lip biopsy showing focal lymphocytic sialadenitis, objective evidence of dry eye (Schirmer’s test or abnormal ocular staining), or objective evidence of salivary gland involvement (salivary flow rate ≤ 0.1 ml/min, defect in ≥ 1 phase of salivary scintigraphy, typical appearance of salivary gland on ultrasound or CT/MRI).

DIFFERENTIAL DIAGNOSIS

—DRY EYES (non-medication related)

• Exposure
  • Allergic conjunctivitis
  • Low humidity
  • Contact lenses
  • Decreased blinking (reading, screen time, driving)
• Inflammatory
  • Uveitis, iritis, rosacea, ocular pemphigoid
• Infectious
  • Herpes keratitis
• Orbital defect
  • Meibomian gland deficiency
  • Eyelid defect (ex: ectropion, proptosis)
  • Cranial neuropathy
• Other
  • Malnourishment with hypovitamintosis,

—DRY MOUTH (non-medication related)

• Glandular
  • Symptomatic Type 2 diabetes
  • Hypoplasia/atrophy of salivary glands
  • Sarcoidosis of salivary glands
• Metabolic
  • Symptomatic Type 2 diabetes
• Infectious
  • Periodontal gingivitis
  • Hepatitis C infection
  • HIV
  • HTLV1
  • Tuberculosis
• Exposure
  • Head and neck radiation, alcoholism
• Anatomic
  • Mouth breathing, nasal obstruction
• Infiltrative
  • Sarcoidosis, IgG4-RD, amyloidosis

—MEDICATIONS CAUSING SICCA

• Anti-histamines
• Alpha-1 antagonists, Alpha-2 agonists, Beta-blockers
• Muscle relaxants: cyclobenzaprine
• Urologic drugs: Oxybutynin
• Parkinson’s drugs: levodopa/carbidopa
• Psychiatric drugs and sedatives: benzodiazepines, SSRIs, tricyclic antidepressants, opioids
• Anticholinergics: atropine, scopolamine

CLASSIFICATION CRITERIA

SjD is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

ACR/EULAR 2016 CRITERIA

—INCLUSION CRITERIA

• At least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following:

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3.  Do you use tear substitutes more than three times a day?
4. Have you had a daily feeling of dry mouth for more than 3 months?
5. Do you frequently drink liquids to aid in swallowing dry food?
6. Or in whom there is suspicion of SjD from the ESSDAI (at least one domain with a positive item).

—EXCLUSION CRITERIA

• History of head and neck radiation treatment
• Active hepatitis C infection (with confirmation by PCR)
• AIDS
• Sarcoidosis
• Amyloidosis
• Graft-versus-host disease
• IgG4-related disease

—CRITERIA

Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm2	3
Anti-SSA/Ro-positive	3
Ocular Staining Score ≥5 (or van Bijsterveld score ≥4) in at least one eye*	1
Schirmer’s test ≤5 mm/5 min in at least one eye*	1
Unstimulated whole saliva flow rate ≤0.1 mL/min*	1

*Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and ocular dryness after a sufficient interval without these medications in order for these components to be a valid measure of oral and ocular dryness.

Classification Criteria are met if score ≥4 when the weights from the five criteria items above are summed

TREATMENT

ASSESSING DISEASE AND TREATMENT RESPONSE

• Goals
  • Glandular: Alleviating glandular symptoms as best as possible
    • Treat ocular and oral dryness
    • Prevent/treat complications such as dental caries and corneal damage
  • Extra-glandular: screening and managing extra-glandular symptoms
    • Including ILD, renal involvement, and neuropathy
• Approach: Clinical Assessment
  • History and review
    • Presence and severity of sicca and systemic features (including joint swelling, rash, muscle weakness, respiratory or neurological symptoms)
  • Exam
    • Signs of glandular dysfunction (ex: parotid gland enlargement); can be supplemented by point-of-care salivary gland ultrasound if done in expert hands,
    • Signs of systemic involvement (ex: petechiae, joint swelling, lymphadenopathy, respiratory crackles, neurological deficits).
  • Lab testing including periodic basic bloodwork
    • CBC for cytopenias
    • SPEP for MGUS
    • Renal function tests (creatinine, urinalysis, urine ACR)
    • Inflammatory markers: CRP
  • Questionnaires: May consider, though more often for research purposes
    • ESSDAI or ESSPRI (see “Disease Measures“, above)

SICCA MANAGEMENT

—ORAL SICCA

• Non-pharmacologic management
  • Gustatory stimulants:
    Sugar-free acidic candies, malic acid lozenges, xylitol
  • Mechanical stimulants:
    Sugar-free chewing gum (if residual salivary gland function)
  • Prevention:
    Excellent oral hygiene, avoid sweetened/acidic foods/beverages, regular dental checks, tobacco-use cessation
  • Replacement:
    Saliva substitute (ex: gel, mouth rinse) of neutral pH with fluoride and electrolytes
• Pharmacologic management
  • Muscarinic agonists:
    • Pilocarpine 2.5-5.0 mg/d, uptitrate weekly as tolerated until  5 mg QID (meals and bedtime)
    • Pilocarpine 4% ocular drops 2-3 drops under tongue is equivalent to 4-6mg oral pilocarpine
    • Cevimeline 30mg TID (not available in Canada)
• Candidiasis
  • Oral candidiasis is frequent comorbidity with oral sicca
  • Topical nystatin mouth wash, may need oral fluconazole if erythematous infection
  • Candidal angular cheilitis: ketoconazole or miconazole cream topically for 2 weeks

—OCULAR SICCA

• Non-pharmacological management
  • Smoking cessation: smoking linked to dry eye disease
  • Replacement:
    • Drops: preservative-free lubricating drops containing methylcellulose or hyaluronate, Frequency can be individualized based on symptoms from BID to hourly
    • Gels: qHS followed by morning lid hygiene to prevent blepharitis
• Pharmacological management
  • Referral: co-manage with an ophthalmologist that has experience with corneal disease
  • Topical immunomodulators: topical cyclosporine A (0.05%); short-term topical steroids for severe inflammation
  • Topical replacement: autologous or allogenic serum tear drops (inconsistent evidence for benefit)
  • Rescue therapy: Punctal plugs
  • Oral muscarinics: may help ocular outcomes
  • Not recommended: hydroxychloroquine, rituximab, or other systemic immunomodulators

—SYSTEMIC DRYNESS

• Dry cough: humidification of air, consider pilocarpine; evaluate for ILD depending on suspicion
• Vaginal dryness: consider combination with topical estrogen creams or pessaries in post-menopausal patients

SYSTEMIC MANAGEMENT

Systemic immunotherapies should be restricted to patients with active systemic disease, tailored to the specific organ involved

ESSDAI may be used to evaluate severity to help guide treatment

Evidence to support treatment decisions is minimal

• GLANDULAR
  Flare of parotid swelling
  • First Line:
    Parotid massage, Prednisone 0.5-1 mg/kg/day for 2-4 weeks, followed by a taper
  • Second Line:
    May consider rituximab or belimumab off-label. Rule out neoplasia (lymphoma) especially if unilateral glandular swelling.
• INFLAMMATORY ARTHRITIS
  • First line:
    NSAIDs for short period, hydroxychloroquine 5mg/kg/d
  • Second line
    Methotrexate 15-25mg/week or leflunomide 20mg/d
  • Third line
    Rituximab 1g IV Day 1 and Day 15 (limited evidence)
• MIXED CRYOGLOBULINEMIC VASCULITIS
  • First line
    • See Cryoglobulinemic vasculitis chapter
    • Rituximab 375 mg/m2 weekly ×4 or 1g Day 1 and 15 ± Prednisone 1mg/kg/d (max 60-80mg) + taper
  • Subsequent line
    • Referral to centre of expertise to consider rituximab, belimumab, cyclophosphamide, PLEX
• CUTANEOUS
  • Cutaneous lupus:
    Topical steroids/tacrolimus, hydroxychloroquine 5mg/kg/day ± prednisone 0.3mg/kg/d <4 weeks
  • Hypergammaglobulinemic purpura:
    Hdroxychloroquine 5mg/kg/day ± prednisone 0.2mg/kg/d, RTX off-label if refractory
• PULMONARY: Chronic ILD
  • First Line
    • Prednisone 0.5-1.0mg/kg/d
      • Roughly tapered to 7.5-12.5mg/day by 12 weeks, and 5mg/d by ~15-20 weeks
        
        PLUS:
      • Mycophenolate mofetil 1.0-1.5g BID
        OR
        Azathioprine 2mg/kg/d
  • If Progression
    • “Inflammatory” CT pattern: Add/switch immunosuppression
      (ex: ground glass, consolidation)
      • Rituximab, tacrolimus, or JAKi
      • Cyclophosphamide
    • “Fibrotic” CT pattern: Add anti-fibrotic
      (ex: traction bronchiectasis, reticular opacities, honeycombing)
      • Nintendanib (consider Pirfenidone, if not tolerated)
    • Lung Transplant
      • Refer early if high risk for evaluation
• PULMONARY: Rapidly Progressive ILD
  • First Line
    • Methylprednisolone IV pulse, then Prednisone 1mg/kg/d
      AND
    • 1or2 of
      • RTX, CYC, MMF, CNI, JAKi
  • Additional Management
    • ECMO: evaluate candidacy, as bridge to transplant or recovery
    • Lung transplant: evaluate candidacy, if isolated respiratory failure
    • Salvage therapy: PLEX, IVIG
• RENAL
  • TIN or GN
    • Prednisone 0.5-1.0 mg/kg/d tapered off over 6 months, plus
    • Consider Rituximab, cyclophosphamide, mycophenolate mofetil, azathioprine
  • Cryoglobulinemic GN
    • See cryoglobulinemic vasculitis
    • Rituximab 375 mg/m2 weekly ×4 or 1g Day 1 and 15 ± Prednisone 1mg/kg/d (max 60-80mg) + taper
• MYOSITIS
  • Prednisone 0.5-1.0mg/kg/d, plus
  • Methotrexate, mycophenolate mofetil, azathioprine, rituximab, IVIG (treatment similar to other IIM; excluding IBM)
• NEUROLOGICAL
  • Peripheral nervous system
    • Pure sensory small fiber neuropathy
      • No immunosuppression: symptomatic treatment
    • Cryoglobulinemia-related multiple mononeuropathy or axonal sensory-motor neuropathy
      • See cryoglobulinemic vasculitis
      • Rituximab 375 mg/m2 weekly × 4 or 1000 mg Day 1 and 15 ± corticosteroid bolus if severe
      • PLEX can be considered in severe cases
    • CIDP
      • IVIG 2g/kg over 2-5 days q4-6 weeks, in shared care model with neurology
    • Ganglionopathies
      • No immunosuppression; may consider rituximab, IVIG, mycophenolate mofetil, cyclophosphamide. Treatment often individualized based on patient response.
  • Central Nervous System
    • Myelitis or vasculitis: cyclophosphamide or rituximab + corticosteroids
    • Neuromyelitis optica: Rituximab + corticosteroids, consider PLEX.
      • Maintenance therapy with azathioprine or mycophenolate mofetil can also be considered
• HEMATOLOGICAL
  • Autoimmune thrombocytopenia
    Treat as similar to usual ITP: If < 30,000/mm3 or bleeding
    • First line:
      • Dexamethasone 40mg x 4 days or prednisone 0.5-1mg/kg/d taper over 6 weeks ± if bleeding: intravenous immunoglobulins (1 g/kg D1 and D2) one course
    • Second line:
      • Rituximab
    • Refractory
      • thrombopoietin receptor agonists (ex: eltrombopag) can be considered
  • Autoimmune hemolytic anemia
    • First line:
      Prednisone 0.5-1.0 mg/kg depending on severity) reduction over 3 months
    • Second line:
      Rituximab
  • MALT lymphoma
    • Treat in shared care with oncology; tailored based on extent of disease and patient comorbidities.
    • Rituximab + alkylating agent (chlorambucil or bendamustine), or
    • Rituximab + fludarabine purine analogue
• PREGNANCY
  Treat similar to pregnancy in anti-Ro/SSA positive systemic lupus
  • Plan pregnancy, maintain stable systemic disease state
  • Hydroxychloroquine 5mg/kg/day may reduce rates of congenital heart block
  • Fetal echocardiogram ~week 16-28 gestation or week 18-26 for surveillance of fetal heart block
  • If 1st, 2nd (?3rd) degree heart block, may benefit from dexamethasone in shared care with maternal fetal medicine. IVIG can be considered in refractory cases

PROGNOSIS

• Poor Prognosticators
  • Male sex
  • Parotid gland enlargement, abnormal parotid scintigraphy
  • Hypocomplementemia, particularly low C4
  • Cryoglobulinemia
  • Vasculitis
• Main causes of death associated with excess mortality
  • B-cell lymphoma
  • Interstitial lung disease
  • Renal failure (less common)
  • Severe cryoglobulinaemic vasculitis
  • Infections
  • Cardiovascular disease
• Mortality
  • Standardized mortality ratio varies depending on the cohort and study design.
  • Standardized mortality ratios reported in literature
    • 1.38 (95% CI 0.94, 2.01)
    • 1.46 (95% CI 1.10, 1.93)

REFERENCES

Akpek, E. K., Mathews, P., Hahn, S., Hessen, M., Kim, J., Grader-Beck, T., Birnbaum, J., & Baer, A. N. (2015). Ocular and systemic morbidity in a longitudinal cohort of Sjögren’s syndrome. Ophthalmology, 122(1), 56–61. https://doi.org/10.1016/j.ophtha.2014.07.026

Baldini C, Fulvio G, La Rocca G, Ferro F. Update on the pathophysiology and treatment of primary Sjögren syndrome. Nat Rev Rheumatol. 2024 Aug;20(8):473-491. doi: 10.1038/s41584-024-01135-3. Epub 2024 Jul 9. PMID: 38982205.

Brito-Zerón, P., Baldini, C., Bootsma, H., Bowman, S. J., Jonsson, R., Mariette, X., Sivils, K., Theander, E., Tzioufas, A., & Ramos-Casals, M. (2016). Sjögren syndrome. Nature reviews. Disease primers, 2, 16047. https://doi.org/10.1038/nrdp.2016.47

Brito-Zerón, P., Acar-Denizli, N., Zeher, M., Rasmussen, A., Seror, R., Theander, E., Li, X., Baldini, C., Gottenberg, J. E., Danda, D., Quartuccio, L., Priori, R., Hernandez-Molina, G., Kruize, A. A., Valim, V., Kvarnstrom, M., Sene, D., Gerli, R., Praprotnik, S., Isenberg, D., … EULAR-SS Task Force Big Data Consortium (2017). Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren’s syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium. Annals of the rheumatic diseases, 76(6), 1042–1050. https://doi.org/10.1136/annrheumdis-2016-209952

Chung, A., Wilgus, M. L., Fishbein, G., & Lynch, J. P., 3rd (2019). Pulmonary and Bronchiolar Involvement in Sjogren’s Syndrome. Seminars in respiratory and critical care medicine, 40(2), 235–254. https://doi.org/10.1055/s-0039-1688448

Devauchelle-Pensec, V., Mariette, X., Benyoussef, A. A., Boisrame, S., Cochener, B., Cornec, D., Nocturne, G., Gottenberg, J. E., Hachulla, E., Labalette, P., Le Guern, V., M’Bwang Seppoh, R., Morel, J., Orliaguet, M., Saraux, A., Seror, R., Costedoat-Chalumeau, N., & Collaborators (2023). French national diagnostic and care protocol for Sjögren’s disease. La Revue de medecine interne, 44(8), 423–457. https://doi.org/10.1016/j.revmed.2023.07.001

François, H., & Mariette, X. (2016). Renal involvement in primary Sjögren syndrome. Nature reviews. Nephrology, 12(2), 82–93. https://doi.org/10.1038/nrneph.2015.174

Huang, H., Xie, W., Geng, Y., Fan, Y., & Zhang, Z. (2021). Mortality in patients with primary Sjögren’s syndrome: a systematic review and meta-analysis. Rheumatology (Oxford, England), 60(9), 4029–4038. https://doi.org/10.1093/rheumatology/keab364

Kanellopoulos, P., Baltoyiannis, C., & Tzioufas, A. G. (2002). Primary Sjögren’s syndrome associated with inclusion body myositis. Rheumatology (Oxford, England), 41(4), 440–444. https://doi.org/10.1093/rheumatology/41.4.440

Lee, A. S., Scofield, R. H., Hammitt, K. M., Gupta, N., Thomas, D. E., Moua, T., Ussavarungsi, K., St Clair, E. W., Meehan, R., Dunleavy, K., Makara, M., Carsons, S. E., Carteron, N. L., & Consensus Expert Panel (CEP) Members (2021). Consensus Guidelines for Evaluation and Management of Pulmonary Disease in Sjögren’s. Chest, 159(2), 683–698. https://doi.org/10.1016/j.chest.2020.10.011

Liampas, A., Parperis, K., Erotocritou, M. F., Nteveros, A., Papadopoulou, M., Moschovos, C., Akil, M., Coaccioli, S., Hadjigeorgiou, G. M., Hadjivassiliou, M., & Zis, P. (2023). Primary Sjögren syndrome-related peripheral neuropathy: A systematic review and meta-analysis. European journal of neurology, 30(1), 255–265. https://doi.org/10.1111/ene.15555

Lovgach, O. R., Plaza, Z., Castro, M. F., Rosas, J., Martínez-Taboada, V., Olivé, A., Almagro, R. M., Benavente, B. S., Font-Urgelles, J., Garcia-Aparicio, A., Manrique-Arija, S., Garcia-Vadillo, A., Lopez-Gonzalez, R., García, J. N., Rodriguez-Lozano, M. B., Galisteo, C., Gonzalez-Martin, J. J., Vela-Casasempere, P., Bohorquez, C., Erausquin, C., … Sánchez, J. L. A. (2025). Mortality in Patients With Sjögren Disease: A Prospective Cohort Study Identifying Key Predictors. The Journal of rheumatology, 52(3), 257–262. https://doi.org/10.3899/jrheum.2024-1033

Luppi, F., Sebastiani, M., Silva, M., Sverzellati, N., Cavazza, A., Salvarani, C., & Manfredi, A. (2020). Interstitial lung disease in Sjögren’s syndrome: a clinical review. Clinical and experimental rheumatology, 38 Suppl 126(4), 291–300.

Nguyen, Y., Beydon, M., Gottenberg, J. E., Morel, J., Perdriger, A., Dernis, E., Cornec, D., Devauchelle-Pensec, V., Sène, D., Dieudé, P., Couderc, M., Fauchais, A. L., Larroche, C., Vittecoq, O., Salliot, C., Hachulla, E., Le Guern, V., Mariette, X., Seror, R., & Nocturne, G. (2024). Distinct Pathophysiologic Pathways Support Stratification of Sjögren’s Disease Based on Symptoms, Clinical, and Routine Biological Data. Arthritis & rheumatology (Hoboken, N.J.), 10.1002/art.43096. Advance online publication. https://doi.org/10.1002/art.43096

Nguyen, Y., Nocturne, G., Henry, J., Ng, W. F., Belkhir, R., Desmoulins, F., Bergé, E., Morel, J., Perdriger, A., Dernis, E., Devauchelle-Pensec, V., Sène, D., Dieudé, P., Couderc, M., Fauchais, A. L., Larroche, C., Vittecoq, O., Salliot, C., Hachulla, E., Le Guern, V., … Seror, R. (2024). Identification of distinct subgroups of Sjögren’s disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts. The Lancet. Rheumatology, 6(4), e216–e225. https://doi.org/10.1016/S2665-9913(23)00340-5

Nishishinya, M. B., Pereda, C. A., Muñoz-Fernández, S., Pego-Reigosa, J. M., Rúa-Figueroa, I., Andreu, J. L., Fernández-Castro, M., Rosas, J., & Loza Santamaría, E. (2015). Identification of lymphoma predictors in patients with primary Sjögren’s syndrome: a systematic literature review and meta-analysis. Rheumatology international, 35(1), 17–26. https://doi.org/10.1007/s00296-014-3051-x

Nocturne, G., Virone, A., Ng, W. F., Le Guern, V., Hachulla, E., Cornec, D., Daien, C., Vittecoq, O., Bienvenu, B., Marcelli, C., Wendling, D., Amoura, Z., Dhote, R., Lavigne, C., Fior, R., Gottenberg, J. E., Seror, R., & Mariette, X. (2016). Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary Sjögren’s Syndrome. Arthritis & rheumatology (Hoboken, N.J.), 68(4), 977–985. https://doi.org/10.1002/art.39518

Price, E. J., Rauz, S., Tappuni, A. R., Sutcliffe, N., Hackett, K. L., Barone, F., Granata, G., Ng, W. F., Fisher, B. A., Bombardieri, M., Astorri, E., Empson, B., Larkin, G., Crampton, B., Bowman, S. J., & British Society for Rheumatology Standards, Guideline and Audit Working Group (2017). The British Society for Rheumatology guideline for the management of adults with primary Sjögren’s Syndrome. Rheumatology (Oxford, England), 56(10), 1828. https://doi.org/10.1093/rheumatology/kex375

Price, E. J., & Baer, A. N. (2021). How to treat Sjögren’s syndrome. Rheumatology (Oxford, England), 60(6), 2574–2587. https://doi.org/10.1093/rheumatology/key363

Psianou, K., Panagoulias, I., Papanastasiou, A. D., de Lastic, A. L., Rodi, M., Spantidea, P. I., Degn, S. E., Georgiou, P., & Mouzaki, A. (2018). Clinical and immunological parameters of Sjögren’s syndrome. Autoimmunity reviews, 17(10), 1053–1064. https://doi.org/10.1016/j.autrev.2018.05.005

Qin, B., Wang, J., Yang, Z., Yang, M., Ma, N., Huang, F., & Zhong, R. (2015). Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Annals of the rheumatic diseases, 74(11), 1983–1989. https://doi.org/10.1136/annrheumdis-2014-205375

Ramos-Casals, M., Brito-Zerón, P., Bombardieri, S., Bootsma, H., De Vita, S., Dörner, T., Fisher, B. A., Gottenberg, J. E., Hernandez-Molina, G., Kocher, A., Kostov, B., Kruize, A. A., Mandl, T., Ng, W. F., Retamozo, S., Seror, R., Shoenfeld, Y., Sisó-Almirall, A., Tzioufas, A. G., Vitali, C., … EULAR-Sjögren Syndrome Task Force Group (2020). EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies. Annals of the rheumatic diseases, 79(1), 3–18. https://doi.org/10.1136/annrheumdis-2019-216114

Retamozo, S., Acar-Denizli, N., Rasmussen, A., Horváth, I. F., Baldini, C., Priori, R., Sandhya, P., Hernandez-Molina, G., Armagan, B., Praprotnik, S., Kvarnstrom, M., Gerli, R., Sebastian, A., Solans, R., Rischmueller, M., Pasoto, S. G., Valim, V., Nordmark, G., Kruize, A., Nakamura, H., … Sjögren Big Data Consortium (2019). Systemic manifestations of primary Sjögren’s syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patients. Clinical and experimental rheumatology, 37 Suppl 118(3), 97–106.

Seror, R., Bowman, S. J., Brito-Zeron, P., Theander, E., Bootsma, H., Tzioufas, A., Gottenberg, J. E., Ramos-Casals, M., Dörner, T., Ravaud, P., Vitali, C., Mariette, X., Asmussen, K., Jacobsen, S., Bartoloni, E., Gerli, R., Bijlsma, J. W., Kruize, A. A., Bombardieri, S., Bookman, A., … Vollenweider, C. (2015). EULAR Sjögren’s syndrome disease activity index (ESSDAI): a user guide. RMD open, 1(1), e000022. https://doi.org/10.1136/rmdopen-2014-000022

Seror, R., Nocturne, G., & Mariette, X. (2021). Current and future therapies for primary Sjögren syndrome. Nature reviews. Rheumatology, 17(8), 475–486. https://doi.org/10.1038/s41584-021-00634-x

Shiboski, C. H., Shiboski, S. C., Seror, R., Criswell, L. A., Labetoulle, M., Lietman, T. M., Rasmussen, A., Scofield, H., Vitali, C., Bowman, S. J., Mariette, X., & International Sjögren’s Syndrome Criteria Working Group (2017). 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren’s syndrome: A consensus and data-driven methodology involving three international patient cohorts. Annals of the rheumatic diseases, 76(1), 9–16. https://doi.org/10.1136/annrheumdis-2016-210571

Singh, A. G., Singh, S., & Matteson, E. L. (2016). Rate, risk factors and causes of mortality in patients with Sjögren’s syndrome: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford, England), 55(3), 450–460. https://doi.org/10.1093/rheumatology/kev354

Sisó-Almirall, A., Meijer, J. M., Brito-Zerón, P., Conangla, L., Flores-Chavez, A., González de Paz, L., Bootsma, H., & Ramos-Casals, M. (2021). Practical guidelines for the early diagnosis of Sjögren’s syndrome in primary healthcare. Clinical and experimental rheumatology, 39 Suppl 133(6), 197–205. https://doi.org/10.55563/clinexprheumatol/pal3z7

Thurtle, E., Grosjean, A., Steenackers, M., Strege, K., Barcelos, G., & Goswami, P. (2023). Epidemiology of Sjögren’s: A Systematic Literature Review. Rheumatology and therapy, 10.1007/s40744-023-00611-8. Advance online publication. https://doi.org/10.1007/s40744-023-00611-8

Vivino, F. B., Bunya, V. Y., Massaro-Giordano, G., Johr, C. R., Giattino, S. L., Schorpion, A., Shafer, B., Peck, A., Sivils, K., Rasmussen, A., Chiorini, J. A., He, J., & Ambrus, J. L., Jr (2019). Sjogren’s syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clinical immunology (Orlando, Fla.), 203, 81–121. https://doi.org/10.1016/j.clim.2019.04.009

Zhan, Q., Zhang, J., Lin, Y., Chen, W., Fan, X., & Zhang, D. (2023). Pathogenesis and treatment of Sjogren’s syndrome: Review and update. Frontiers in immunology, 14, 1127417. https://doi.org/10.3389/fimmu.2023.1127417