How should I screen for connective tissue disease?

Screening for Connective Tissue Disorders

All patients with suspected connective tissue disease (CTD) should undergo baseline screening with antinuclear antibody (ANA) testing, and those with specific CTD diagnoses—particularly systemic sclerosis, inflammatory myopathies, and mixed connective tissue disease—require immediate high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) at diagnosis, regardless of respiratory symptoms. 1, 2

Initial Clinical Assessment

Key Clinical Features to Identify

• Raynaud's phenomenon: Present in the majority of CTD patients and may precede other manifestations by years; assess severity, age at onset, and associated digital changes 3, 4
• Skin manifestations: Look for malar rash, photosensitivity, puffy fingers, sclerodactyly, Gottron's rash, digital tip pitting scars, or ulcerations 5, 6
• Musculoskeletal symptoms: Evaluate for inflammatory arthritis, arthralgias, myalgia, or muscle weakness 5, 6
• Oral ulcers and sicca symptoms: Document presence of oral ulcers, dry eyes, or dry mouth 5
• Constitutional symptoms: Assess for fever, fatigue, and weight loss in the context of multi-system involvement 5

Physical Examination Findings

• Auscultate lungs for fine inspiratory "Velcro" crackles, which suggest interstitial lung disease 2
• Examine hands for puffy fingers, digital pitting scars, sclerodactyly, and telangiectasias 3, 6
• Assess skin for rashes, photosensitivity, and cutaneous lesions 5
• Evaluate joints for synovitis and deformities 5

Serological Screening

First-Line Antibody Testing

• Antinuclear antibody (ANA): Order as the initial screening test; a positive result with coarse speckled pattern suggests mixed connective tissue disease 7, 8
• Anti-U1-RNP antibodies: High titers are hallmark of mixed connective tissue disease and predict ILD progression 7, 8
• Extractable nuclear antigen (ENA) panel: Include anti-Ro/SSA, anti-La/SSB, anti-Smith, anti-Scl-70 (topoisomerase), and anti-centromere antibodies 9
• Rheumatoid factor (RF) and anti-CCP antibodies: Essential for rheumatoid arthritis screening, particularly in patients at risk for RA-ILD 9, 1
• Anti-Ro52 antibodies: Associated with increased ILD risk in Sjögren's syndrome and MCTD 9, 1

Risk Stratification Based on Serology

• Positive anti-topoisomerase (Scl-70): High risk for systemic sclerosis-ILD; requires immediate HRCT and close monitoring 9, 2
• Positive anti-centromere: Lower ILD risk but associated with CREST syndrome variant 3
• High-titer anti-U1-RNP: Strong predictor of ILD progression in MCTD; warrants baseline HRCT and PFTs 9, 7
• Anti-synthetase antibodies (anti-Jo-1) or anti-MDA-5: Mandate immediate pulmonary screening in inflammatory myopathies 9, 1

Pulmonary Screening Protocol

Disease-Specific Screening Recommendations

Systemic Sclerosis (All Patients):

• Baseline HRCT of the chest at diagnosis, even if asymptomatic 1, 2
• Baseline PFTs (spirometry with FVC and DLCO) at diagnosis 1, 2
• Repeat PFTs every 6 months for the first 3–4 years after diagnosis 9, 1, 2
• Annual HRCT for the first 3–4 years after diagnosis 9, 2
• Annual echocardiography to screen for pulmonary hypertension 2

Mixed Connective Tissue Disease (All Patients):

• Baseline HRCT and PFTs (spirometry and DLCO) at diagnosis 9, 1
• For SSc phenotype: Follow systemic sclerosis protocol with PFTs every 6 months and annual HRCT for first 3–4 years 9
• For other phenotypes: Annual clinical examination and PFTs, with HRCT if abnormalities detected 9

Inflammatory Myopathies (All Patients):

• Baseline HRCT and PFTs at diagnosis 9, 1
• Increased monitoring frequency if anti-synthetase or anti-MDA-5 antibodies present 9, 1

Rheumatoid Arthritis (High-Risk Patients Only):

• Screen patients who are male, age >58 years at disease onset, have high disease activity (DAS28-ESR >4.3), smoking history, or high-titer RF/anti-CCP 9, 1
• Clinical auscultation for Velcro crackles; obtain PFTs if risk factors or symptoms present 9, 1
• Proceed to HRCT if PFTs abnormal or clinical suspicion high 9, 1
• Consider using the Juge risk score to stratify ILD risk 1

Sjögren's Syndrome with Anti-Ro52 Positivity:

• Consider pulmonary screening with HRCT and PFTs due to increased ILD risk 9, 1

Why HRCT Is Mandatory

• HRCT is the gold standard for ILD detection across all CTD populations 1, 2
• Chest radiography is inadequate: Low sensitivity and misses mild disease; not recommended for screening 9, 1, 2
• PFTs alone miss significant disease in up to 62.5% of cases 2
• ILD may be asymptomatic at presentation, particularly in systemic sclerosis where it is the leading cause of death 2

Additional Screening Modalities

• Nailfold capillaroscopy: Abnormal capillary patterns increase risk for CTD evolution, particularly systemic sclerosis 4
• 6-minute walk test with pulse oximetry: Assess exercise capacity and oxygen desaturation 2
• Esophageal motility studies: Consider in systemic sclerosis and MCTD, as esophageal dysfunction predicts ILD risk 9, 7
• Echocardiography: Screen for pulmonary hypertension, especially with isolated low DLCO or in symptomatic patients 9, 2

High-Risk Features Requiring Immediate Referral

• Male sex, older age, smoking history, or Black race in systemic sclerosis 9, 2
• Diffuse cutaneous involvement in systemic sclerosis 9, 2
• Early disease (first 3–5 years after CTD diagnosis) 9, 2
• Baseline FVC <70–80% predicted or reduced DLCO 9, 2
• >20% disease extent on HRCT or honeycombing/UIP pattern 9, 2
• High-titer anti-topoisomerase, anti-U1-RNP, anti-synthetase, or anti-MDA-5 antibodies 9, 7

Common Pitfalls to Avoid

• Do not rely on chest X-ray alone: Up to 10% of ILD patients have normal chest radiographs 2
• Do not wait for symptoms: ILD is often asymptomatic early and may be present in 40–80% of MCTD patients at diagnosis 9, 7
• Do not use PFTs as sole screening tool: HRCT detects subclinical abnormalities missed by PFTs 2
• Do not delay HRCT in high-risk patients: The first 3–5 years after CTD diagnosis carry the greatest ILD risk 9, 2
• Avoid invasive procedures: Bronchoscopy, surgical lung biopsy, or cryobiopsy are not recommended for CTD-ILD diagnosis 2

Multidisciplinary Approach

• Integrate rheumatology, pulmonology, and radiology expertise for diagnosis and severity assessment of CTD-ILD 2
• Prompt rheumatology referral is indicated when imaging or functional testing reveals ILD in the context of autoimmune features 1