Sjogren syndrome

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Sjogren disease is a systemic autoimmune condition in which exocrine-gland dysfunction produces dry eyes and mouth, while B-cell and immune-complex pathways can affect lungs, kidneys, nerves, joints, vessels and blood cells. Symptoms are common in the general population, so diagnosis requires a coherent phenotype and objective evidence rather than dryness or ANA positivity alone. Use the term secondary association descriptively when another autoimmune disease coexists, but do not assume systemic risk disappears.

The 2016 ACR/EULAR classification system gives weighted importance to anti-Ro positivity and focal lymphocytic sialadenitis on minor salivary-gland biopsy, with ocular staining, Schirmer and salivary flow contributing. It excludes several mimics. Classification assists consistency but individual diagnosis and biopsy interpretation require specialist expertise. Anti-La without anti-Ro is less specific. Salivary ultrasound can support assessment in experienced services but is not interchangeable with every established criterion.

Local management protects tissue as well as comfort. Preservative-free tear replacement is safest when drops are frequent; ophthalmology treats inflammatory ocular-surface disease and complications. Oral care combines hydration, saliva stimulation where function remains, neutral-pH substitutes, high-fluoride dental prevention and candidiasis treatment when proven. Pilocarpine can increase tears and saliva but causes cholinergic effects and is unsuitable in uncontrolled asthma or relevant cardiac disease.

Fatigue and pain require a broad formulation: inflammation, sleep, thyroid, anaemia, autonomic dysfunction, neuropathy, mood, menopause and fibromyalgia may coexist. Systemic immunosuppression is reserved for defined organ activity and follows the threatened organ. Long-term surveillance prioritises lymphoma signals, pulmonary symptoms, neuropathy, kidney acid-base disturbance, dental and ocular damage, pregnancy antibodies and the cumulative harm of treatments.

Key points

Ask about gritty or burning eyes, reduced tears, water needed to swallow dry food, nocturnal drinking, dental decay, gland swelling, vaginal dryness, fatigue and systemic symptoms.
Review anticholinergic and drying medicines, hydration, diabetes, thyroid disease, hepatitis C, HIV, sarcoidosis, IgG4 disease, radiotherapy and local ocular or salivary disorders before applying an autoimmune label.
Anti-Ro supports Sjogren disease but is neither universally present nor sufficient; objective ocular testing, unstimulated salivary flow and minor salivary-gland biopsy provide complementary evidence.
Use validated 2016 ACR/EULAR criteria to organise objective findings, but diagnosis remains clinical and criteria are not a substitute for excluding mimics.
Treat eyes stepwise with preservative-free lubricants, lid care and ophthalmology-directed anti-inflammatory or serum options when surface disease persists; urgent pain, photophobia or visual loss needs same-day review.
For mouth dryness use frequent water, saliva substitutes, sugar-free gum when residual function exists and pilocarpine in suitable patients; avoid sugary acidic sweets that worsen caries.
Arrange high-fluoride dental prevention, meticulous interdental care and regular dental review because symptom relief alone does not replace remineralisation and plaque control.
Do not use hydroxychloroquine routinely for dryness or fatigue without objective inflammatory disease; systemic treatment is matched to arthritis, lung, renal, neurological, vasculitic or haematological involvement.
Persistent salivary-gland enlargement, lymphadenopathy, purpura, low C4, cryoglobulin, monoclonal protein, cytopenia or systemic decline requires lymphoma assessment.
Test anti-Ro and anti-La before pregnancy planning and coordinate hydroxychloroquine and fetal-heart surveillance with rheumatology and maternal medicine.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Polygenic autoimmune susceptibility

HLA and immune-regulatory variants interact with sex-related factors and environmental exposures, producing loss of tolerance rather than a single inherited cause.

Primary or associated disease

Sjogren disease may occur alone or alongside rheumatoid arthritis, lupus, systemic sclerosis, autoimmune thyroid disease and other immune disorders.

Possible mucosal triggers

Viral and other mucosal stimuli may activate interferon and B-cell pathways in susceptible salivary tissue, although no persistent infection explains most established disease.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Exocrine immune infiltration
T and B lymphocytes infiltrate lacrimal and salivary glands, disrupt acinar function and ducts and progressively reduce tear and saliva production.
2
B-cell hyperactivity
BAFF-driven B-cell activation generates anti-Ro, anti-La, hypergammaglobulinaemia, cryoglobulins and occasional monoclonal evolution, linking systemic disease with lymphoma risk.
3
Surface injury
Loss of the aqueous tear film injures corneal and conjunctival epithelium, while reduced saliva removes lubrication, buffering, antimicrobial and remineralising protection.
4
Systemic immune disease
Immune-complex vasculitis, lymphocytic infiltration and antibody-associated mechanisms can affect nerves, lungs, kidneys, joints, blood cells and other organs beyond dryness.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Ocular sicca

Daily gritty, burning or foreign-body sensation, redness and fluctuating vision with reduced tear production suggests keratoconjunctivitis sicca after ocular mimics are reviewed.

Oral sicca

Needing fluid for dry food, waking to drink, loss of saliva pool, fissured tongue and disproportionate cervical caries indicates clinically important salivary hypofunction.

Salivary gland diseaseRed flag

Recurrent bilateral soft swelling may accompany disease, while persistent unilateral firmness or nodes demands infection, obstruction and lymphoma investigation.

Systemic immune pattern

Raynaud, inflammatory joints, palpable purpura, neuropathy, cough, dyspnoea, renal tubular acidosis or glomerular urine findings extend assessment beyond dryness.

Vasculitic neuropathyRed flag

Acute painful asymmetric sensory or motor deficits, foot drop or mononeuritis multiplex is organ-threatening and requires urgent neurological-rheumatology assessment.

Lymphoma risk cluster

Persistent gland enlargement, purpura, low C4, cryoglobulinaemia, monoclonal gammopathy, splenomegaly and cytopenia should lower the biopsy threshold.

Red flags requiring action

Persistent, hard or asymmetric parotid or submandibular enlargement, lymph nodes, splenomegaly, weight loss or night sweats requires urgent lymphoma assessment.
Palpable purpura, low C4, cryoglobulinaemia, monoclonal gammopathy or persistent cytopenia identifies higher systemic and lymphoma risk.
New foot drop, rapidly progressive sensory loss, severe neuropathic pain or autonomic failure may indicate vasculitic neuropathy requiring urgent treatment.
Haematuria, proteinuria, declining eGFR, acidosis, hypokalaemia or stones suggests glomerulonephritis or tubulointerstitial renal disease.
A painful photophobic red eye, corneal defect or reduced vision needs urgent ophthalmology because severe dryness can ulcerate or infect the cornea.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Anti-Ro, anti-La, ANA, RF and immunoglobulinsFirst step
Why
Support autoimmune classification and identify B-cell activation or monoclonal change.
Interpretation and limitations
Anti-Ro carries the greatest classification weight; seronegative disease remains possible, while isolated ANA, RF or anti-La cannot establish diagnosis.
02
Schirmer test and ocular surface staining
Why
Objectively measure aqueous tear production and epithelial damage through ophthalmic assessment.
Interpretation and limitations
Schirmer of 5 mm or less in five minutes and abnormal staining contribute to classification; contact lenses, drops and local eye disease affect results.
03
Unstimulated whole salivary flow
Why
Quantify salivary hypofunction before attributing symptoms to autoimmune gland disease.
Interpretation and limitations
A flow of 0.1 mL/min or less is a classification item, but medicines, hydration, smoking and collection technique require control.
04
Labial minor salivary-gland biopsy
Why
Identify focal lymphocytic sialadenitis when diagnosis remains uncertain or serology is negative.
Interpretation and limitations
A focus score of at least one per 4 mm² carries major classification weight; expert pathology must separate characteristic inflammation from nonspecific chronic damage.
05
FBC, renal profile, bicarbonate, urine, C3 and C4
Why
Screen cytopenia, distal renal tubular acidosis, glomerular disease and immune-complex risk.
Interpretation and limitations
Hypokalaemic normal-anion-gap acidosis suggests distal RTA; low C4, proteinuria, haematuria or cytopenia requires systemic and lymphoma review.
06
SPEP, immunofixation, cryoglobulins and imaging
Why
Investigate high-risk gland swelling, purpura, neuropathy or systemic decline for clonal or vasculitic disease.
Interpretation and limitations
Handle cryoglobulin samples warm before processing; image and biopsy the most informative persistent gland or node rather than repeating screening serology.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Medicines and dehydration

Anticholinergics, antidepressants, antihistamines, diuretics, opioids, cannabis, dehydration and mouth breathing commonly reduce secretions without autoimmune gland inflammation.

Age and local gland disease

Age-related change, blepharitis, meibomian dysfunction, obstruction, stones, infection, radiotherapy and surgery can cause ocular or salivary symptoms with different objective patterns.

Metabolic and infectious causes

Diabetes, thyroid disease, hepatitis C, HIV, sarcoidosis and IgG4-related disease can produce sicca, gland enlargement or systemic abnormalities.

Fibromyalgia and sleep disorder

Fatigue, cognitive symptoms and widespread pain may reflect coexisting fibromyalgia, anaemia, thyroid disease, sleep apnoea or depression rather than active systemic inflammation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Confirmatory assessmentObjectify sicca and exclude mimicsFirst stepConfirmatoryPersistent eye or mouth dryness occurs with autoimmune or systemic features.

1Document symptom duration, dental and ocular damage, glands, medicines, hydration and systemic phenotype and test anti-Ro with baseline FBC, renal, urine, complement and immunoglobulins.
2Arrange Schirmer and ocular staining plus unstimulated salivary flow; use minor salivary-gland biopsy when serology or objective findings leave meaningful uncertainty.
3Apply classification evidence after excluding hepatitis C, HIV, sarcoidosis, IgG4 disease, radiotherapy and anticholinergic effects, then agree organ ownership and follow-up.

02First-line surface protectionReplace, stimulate and prevent damageFirst lineDryness is present without current corneal emergency or systemic organ threat.

1Use preservative-free tears at the frequency needed, lid care and environmental measures; refer persistent surface inflammation or frequent-drop need to ophthalmology.
2Use water, neutral-pH saliva substitute, sugar-free gum and pilocarpine when residual function and cardiopulmonary safety permit.
3Arrange high-fluoride dental prevention, interdental cleaning and recall, and diagnose candidiasis or reflux before adding specific treatment.

03Systemic escalationTreat demonstrated organ activityEscalationInflammatory arthritis, ILD, renal, neurological, vasculitic or haematological disease causes objective organ risk.

1Define severity with organ-specific examination, physiology, imaging, urine, biopsy or nerve studies and exclude infection and malignancy.
2Choose glucocorticoid and steroid-sparing therapy by organ, using hydroxychloroquine only for an appropriate inflammatory indication rather than dryness alone.
3Set objective response and taper criteria and involve respiratory, renal, neurology or haematology for major-organ or lymphoma-risk disease.

04Lymphoma pathwayBiopsy persistent high-risk changePersistent gland enlargement, nodes, purpura, low complement, cryoglobulin, monoclonal protein or systemic decline emerges.

1Examine all nodal and salivary sites and obtain FBC, film, LDH, immunoglobulins, SPEP or immunofixation, complement, cryoglobulins and targeted infection tests.
2Arrange ultrasound or cross-sectional imaging to identify a representative gland or node and obtain tissue through the haematology or head-and-neck pathway.
3Do not suppress unexplained swelling repeatedly with glucocorticoid before tissue, because temporary shrinkage can obscure diagnosis.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-line replacement of aqueous tear deficiency and reduction of friction-related ocular-surface injury.

Preservative-free artificial tears

Instil one drop into each symptomatic eye as needed, commonly four to six times daily; use preservative-free single-dose or multidose systems when application exceeds four times daily.

Blurred vision can occur briefly. Persistent pain, photophobia, discharge or reduced vision requires urgent examination; ointment is useful at night but impairs vision and cannot treat infection or severe inflammation.

Muscarinic stimulation increases residual salivary and tear secretion in selected patients with meaningful gland function.

Pilocarpine

Start 5 mg orally three times daily with food and water; if tolerated and still needed, increase to 5 mg four times daily, not exceeding 30 mg/day.

Avoid uncontrolled asthma, acute iritis and important cardiorenal disease; sweating, flushing, urinary frequency, diarrhoea, bradycardia, bronchospasm and visual accommodation effects limit use. Review benefit after two to three months.

Provides enhanced remineralisation and caries prevention when salivary buffering and mineral delivery are impaired.

Sodium fluoride 1.1% toothpaste

Brush with a prescription 5,000 ppm fluoride toothpaste twice daily, spit without rinsing, and avoid eating or drinking for thirty minutes, under dental prescribing and age-appropriate instructions.

For adults and appropriate older adolescents under dental advice; do not swallow, keep away from children and continue professional dental assessment because fluoride does not treat established decay or periodontal disease.

May treat a defined inflammatory musculoskeletal or cutaneous manifestation but is not routine therapy for isolated dryness or non-inflammatory fatigue.

Hydroxychloroquine

For selected inflammatory joint or skin disease, use 200–400 mg orally daily without exceeding 5 mg/kg actual body weight/day, at the minimum effective dose.

Review renal function, maculopathy, QT interactions, hypoglycaemia and cardiomyopathy and arrange risk-based retinal monitoring. It is compatible with pregnancy and breastfeeding under BSR guidance.

Rapid temporary immunosuppression for defined systemic organ activity, not for uncomplicated sicca, fatigue or diffuse pain.

Prednisolone for major-organ disease

Use an organ- and severity-specific specialist dose for the shortest period, with a documented taper and early steroid-sparing treatment; vasculitic neuropathy or glomerulonephritis may require high-dose or intravenous rescue.

Exclude infection and obtain lymphoma tissue first when feasible; monitor glucose, pressure, mood, eyes, bone and infection and avoid abrupt withdrawal after prolonged exposure.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Ocular and dental damage

Keratitis, corneal ulcer or infection, accelerated caries, enamel loss, oral candidiasis, periodontal disease and tooth loss arise when surface protection is inadequate.

B-cell lymphoma

MALT and other non-Hodgkin lymphomas occur more often than in the general population, especially with persistent glands, purpura, low complement or cryoglobulins.

Systemic organ injury

ILD, airway disease, vasculitic neuropathy, renal tubular acidosis, glomerulonephritis, arthritis and cytopenia can cause irreversible morbidity independent of sicca severity.

Pregnancy antibody effects

Maternal anti-Ro or anti-La antibodies can cause fetal conduction disease and neonatal lupus, requiring pre-conception counselling and specialist fetal surveillance.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review ocular symptoms, drop frequency, staining or corneal complications with ophthalmology at an interval matched to surface severity.
Arrange regular dental review for caries, periodontal disease, candidiasis, fluoride use and ability to maintain oral care.
At systemic review examine salivary glands and nodes and record weight, purpura, neuropathy, respiratory symptoms, joints and constitutional change.
Repeat FBC, creatinine, electrolytes, bicarbonate, urine, complement, immunoglobulins and monoclonal or cryoglobulin tests according to systemic and lymphoma risk.
Assess pilocarpine benefit and cholinergic toxicity, and stop if there is no worthwhile dryness or functional improvement.
Before pregnancy document anti-Ro, anti-La, disease activity and medicines and coordinate fetal surveillance and compatible control.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Symptoms and flow can diverge

A patient may report severe dryness with modest objective loss or have dangerously low flow after adapting to symptoms, so measure and inspect damage.

Seronegativity does not end assessment

A convincing phenotype with objective gland dysfunction may need minor salivary-gland biopsy despite negative anti-Ro.

Dryness treatment protects tissue

Tears, fluoride and saliva strategies aim to prevent corneal and dental destruction, not merely improve comfort scores.

Fatigue is multidimensional

Inflammation, sleep, endocrine disease, autonomic dysfunction, mood, menopause and fibromyalgia need separate assessment before immunosuppression.

Parotid swelling has a trajectory

Episodic bilateral swelling can be inflammatory, while persistent unilateral firmness changes the question to obstruction, infection or lymphoma.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing Sjogren disease from ANA positivity and dry mouth without objective testing or a medicine review.
02
Using anti-La alone as if it had the same diagnostic specificity and classification weight as anti-Ro.
03
Treating repeated gland swelling with steroid before excluding stone, bacterial infection and lymphoma.
04
Prescribing hydroxychloroquine for isolated fatigue or dryness without defining an inflammatory treatment target.
05
Focusing on symptom scores while dental caries, corneal injury, renal acidosis or neuropathy progresses.
06
Missing pregnancy anti-Ro or anti-La planning because systemic disease appears clinically mild.