What is the recommended approach to screen an adult, particularly a woman of childbearing age with unexplained multisystem symptoms, for connective tissue disease?

Screening for Connective Tissue Disease

Begin with an antinuclear antibody (ANA) test by indirect immunofluorescence as the initial screening test, followed by targeted disease-specific autoantibody panels guided by clinical features and ANA pattern. 1

Initial Clinical Assessment

Look for specific features that raise suspicion for connective tissue disease (CTD):

Key Clinical Features to Identify

Musculoskeletal manifestations:

• Joint pain or swelling affecting multiple joints 2
• Chronic musculoskeletal pain with morning stiffness 3
• Muscle weakness 2

Skin and vascular findings:

• Raynaud's phenomenon (fingers/toes turning white, blue, then red with cold or stress) 2, 3
• Photosensitivity with rashes after sun exposure 2, 3
• Malar rash or other characteristic rashes 4
• Skin thickening or sclerodactyly 2

Systemic symptoms:

• Unexplained fever 2
• Fatigue 2
• Dry eyes and dry mouth (sicca symptoms) 2, 3
• Progressive dyspnea on exertion 3
• Pleuritis or serositis 2

Critical pitfall: Multi-system involvement with evidence of inflammation but no obvious infectious or malignant cause should strongly raise suspicion for CTD. 2, 4

Laboratory Screening Algorithm

Step 1: Initial Screening Panel

Order these tests for all patients with suspected CTD:

• ANA by indirect immunofluorescence (not ELISA) - this is the essential first-line screening test 1, 2
• Complete blood count with differential (to detect cytopenias, anemia, lymphopenia) 1, 2
• Comprehensive metabolic panel (kidney and liver function) 1, 2
• Inflammatory markers: ESR and CRP 1, 2
• Urinalysis 2

Important caveat: Approximately 20% of patients with active CTD may have normal CRP/ESR, so normal inflammatory markers should not exclude CTD. 2

Step 2: Disease-Specific Autoantibody Testing Based on ANA Pattern and Clinical Features

If ANA is positive with nucleolar pattern or systemic sclerosis suspected (Raynaud's, skin thickening):

• Anti-topoisomerase I (anti-Scl-70) - associated with diffuse disease and interstitial lung disease 1, 2
• Anti-centromere antibody - associated with limited cutaneous systemic sclerosis (CREST) 1, 2
• Anti-RNA polymerase III - associated with diffuse disease and renal crisis 1
• Anti-U3RNP (fibrillarin) - associated with pulmonary arterial hypertension 1

If rheumatoid arthritis suspected (symmetric joint swelling, morning stiffness >1 hour):

• Rheumatoid factor (RF) 1, 2
• Anti-cyclic citrullinated peptide (anti-CCP) antibody - more specific than RF 1, 2

If myositis suspected (proximal muscle weakness, elevated creatine kinase):

• Myositis-specific antibody panel including: 1, 2
  • Anti-synthetase antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ)
  • Anti-MDA-5 (associated with rapidly progressive interstitial lung disease)
  • Anti-Ro52 (associated with increased ILD risk)
• Creatine kinase (CK) 2

If Sjögren's syndrome suspected (dry eyes, dry mouth, parotid swelling):

• Anti-SSA/Ro antibodies 1, 2
• Anti-SSB/La antibodies 1, 2
• Rheumatoid factor 2

If mixed connective tissue disease suspected (overlap features):

• Anti-U1RNP antibody - the defining antibody for MCTD 1

If systemic lupus erythematosus suspected (malar rash, serositis, cytopenias):

• Anti-double stranded DNA (anti-dsDNA) 2
• Anti-Smith antibodies 2
• Complement levels (C3, C4) 2

Step 3: Additional Screening Tests

Infectious disease screening (required before immunosuppressive therapy):

• Hepatitis B surface antigen and core antibody 2
• Hepatitis C antibody 2
• HIV serology 2

Additional tests based on specific clinical scenarios:

• Quantitative immunoglobulin levels (IgG, IgA, IgM) if recurrent infections 2
• ANCA if vasculitis suspected 2
• Thyroid antibodies if thyroid dysfunction present 2

Pulmonary Screening for Interstitial Lung Disease

Critical consideration: Interstitial lung disease (ILD) is a leading cause of mortality in CTD, particularly in systemic sclerosis, and can be present even without respiratory symptoms. 5

Who Needs Pulmonary Screening

Screen all patients with:

• Systemic sclerosis (SSc) - screen at diagnosis even if asymptomatic 5, 2
• Inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome) 5
• Mixed connective tissue disease 5

Screen high-risk patients with:

• Rheumatoid arthritis if: male gender, older age at RA onset (>58 years), high disease activity (DAS28-ESR >4.3), smoking history, high-titer RF or anti-CCP 5
• Sjögren's syndrome with anti-Ro52 antibodies 5

Pulmonary Screening Tests

For systemic sclerosis:

• High-resolution CT (HRCT) chest at diagnosis (even without symptoms) 5, 2
• Pulmonary function tests (PFTs): FVC and DLCO at baseline 5
• Repeat PFTs every 6 months and HRCT annually for first 3-4 years 2

For rheumatoid arthritis:

• Clinical examination with auscultation for Velcro crackles 5
• PFTs if symptoms or risk factors present 5
• HRCT if PFTs abnormal or high clinical suspicion 5
• Consider using the Juge risk score to identify high-risk patients (Table 2 in evidence shows risk stratification by age, sex, and disease activity) 5

For inflammatory myopathies and MCTD:

• HRCT and PFTs at diagnosis 5
• More frequent monitoring if anti-synthetase antibodies or anti-MDA-5 present 5

Important pitfall: Chest radiography is not recommended for ILD screening as it lacks sensitivity. 5 HRCT is the gold standard for detecting ILD. 5, 2

Key Clinical Pearls

• ANA pattern matters: Homogeneous, speckled, nucleolar, and centromere patterns provide critical clues for subsequent specific autoantibody testing. 1
• Myositis-specific antibodies should be ordered regardless of ANA result if clinical features suggest myositis, as some patients may be ANA-negative. 1
• Do not order every available autoantibody test - tailor testing to clinical presentation to avoid false positives and unnecessary costs. 2
• ILD can precede CTD diagnosis by several years in 13-38% of patients, so maintain high suspicion even with incomplete CTD features. 5
• Early but irreversible organ damage can occur asymptomatically in the first 5-7 years after CTD onset, particularly in the lungs. 3

When to Refer to Rheumatology

Refer promptly if:

• Positive ANA with compatible clinical features 1, 2
• Multiple organ system involvement without clear alternative diagnosis 2, 4
• Positive disease-specific autoantibodies (anti-CCP, anti-Scl-70, anti-Jo-1, anti-dsDNA, etc.) 1, 2
• Evidence of ILD on imaging or PFTs in the setting of autoimmune features 5
• Progressive symptoms rather than stable, long-standing issues 3