What are the initial laboratory evaluations and common diagnoses for a patient suspected of having an autoimmune disorder?

Initial Laboratory Evaluation for Suspected Autoimmune Disease

When evaluating a patient with suspected autoimmune disease, begin with inflammatory markers (ESR, CRP), complete blood count with differential, comprehensive metabolic panel, and an autoimmune panel including ANA, RF, and anti-CCP antibodies. 1, 2

Core Laboratory Tests (First-Line)

Inflammatory Markers

• ESR and CRP are highly elevated in inflammatory/autoimmune conditions, while normal or mildly elevated levels suggest non-inflammatory causes 1
• These markers help distinguish autoimmune arthritis from non-inflammatory joint disease 1

Complete Blood Count with Differential

• Assess for cytopenias (anemia, leukopenia, thrombocytopenia) that may indicate systemic lupus erythematosus or other systemic autoimmune diseases 1, 2
• Confirm thrombocytopenia by direct peripheral blood smear examination, as pseudothrombocytopenia can occur due to platelet clumping with EDTA anticoagulant 1
• Lymphopenia may suggest underlying immunodeficiency disorders 3

Autoimmune Panel

• ANA (antinuclear antibody), RF (rheumatoid factor), and anti-CCP antibodies are essential for diagnosing systemic autoimmune diseases and rheumatoid arthritis 1, 2
• Autoantibody positivity alone does not make a diagnosis - nonspecific autoantibodies can be persistently or transiently present at mildly or moderately increased levels 1, 4
• Clinical context is paramount when interpreting autoantibody results 1, 4

Comprehensive Metabolic Panel

• Renal function and liver function tests assess organ involvement in systemic autoimmune diseases 1, 2
• Electrolyte abnormalities may indicate adrenal insufficiency in autoimmune polyendocrine syndromes 3

Disease-Specific Autoantibody Testing

For Suspected Sjögren's Syndrome

• Order SSA (anti-Ro), SSB (anti-La), rheumatoid factor, and ANA when patients have clinically significant dry eye and dry mouth symptoms 3
• A point-of-care test including traditional serology plus additional biomarkers (SP1, CA6, PSP) is available 3

For Suspected Autoimmune Hepatitis

• Test for ANA, SMA (smooth muscle antibody), anti-LKM1, and anti-LC1 antibodies using indirect immunofluorescence as the primary screening method 3
• ELISA alone is inappropriate as the sole screening test for AIH-related autoantibodies 3
• Autoantibody titers may vary during disease course, and repeated testing may allow detection in initially seronegative individuals 3

For Suspected Autoimmune Encephalitis

• CSF analysis and serum testing for antibodies to surface antigens (NMDAR, AMPAR, LGI1, CASPR2, GABA-R) and intracellular antigens should be performed 3
• Brain MRI with contrast is essential to rule out alternative diagnoses and identify anatomical patterns 3

For Suspected Thyroid Disease

• Test for antithyroid peroxidase antibody and antithyroglobulin antibody in patients with features of thyroid dysfunction 3
• Monitor thyroid function (TSH, FT4, TPO-Ab) every 12 months in patients with established autoimmune disease 3

For Suspected Adrenal Insufficiency

• Measure 21-hydroxylase antibodies (21OH-Ab) as the primary aetiologic test for autoimmune primary adrenal insufficiency 3
• If 21OH-Ab-negative, investigate other causes 3

Additional Testing Based on Clinical Presentation

HLA-B27 Testing

• Perform if axial symptoms or entheseal involvement suggest spondyloarthropathy 1

Anti-Cytokine Autoantibodies

• Test for anti-IL-17A, anti-IL-17F, and anti-IL-22 antibodies if chronic mucocutaneous candidiasis is present, suggesting APECED 1, 4

Genetic Testing

• Order IL1RN and IL36RN mutation analysis if early-onset severe pustular skin disease suggests DIRA or DITRA 1, 4
• Perform PSTPIP1 gene analysis when pyogenic arthritis occurs with ulcerative skin lesions and cystic acne (PAPA syndrome) 1, 4

Screening for Associated Autoimmune Conditions

Annual Monitoring in Established Autoimmune Disease

• Screen for diabetes mellitus with plasma glucose and HbA1c 3
• Monitor for B12 deficiency due to autoimmune gastritis 3
• Test for coeliac disease (tissue transglutaminase 2 autoantibodies and total IgA) in patients with frequent or episodic diarrhea 3
• Screen for viral hepatitis B, C, and latent/active tuberculosis before initiating DMARD treatment if severe disease requires immunosuppression 1

Critical Diagnostic Pitfalls

• Exclude infectious, malignant, and other causes before diagnosing autoimmune or autoinflammatory syndromes 1, 4
• Consider drug-induced causes (quinidine, heparin, sulfonamides, aspirin) which may cause or exacerbate symptoms 1
• Recognize that some autoantibodies have low clinical relevance (e.g., VGKC, VGCC) and should not drive diagnosis alone 3
• Repeated autoantibody testing may be necessary as seronegative individuals at diagnosis may express conventional autoantibodies later 3

Common Autoimmune Diagnoses by Organ System

Systemic Autoimmune Diseases

• Systemic lupus erythematosus (ANA, anti-dsDNA, anti-Smith) 2
• Rheumatoid arthritis (RF, anti-CCP) 1, 2
• Sjögren's syndrome (SSA, SSB) 3
• Systemic sclerosis/CREST syndrome (anti-centromere, anti-Scl-70) 5

Organ-Specific Autoimmune Diseases

• Autoimmune hepatitis (ANA, SMA, anti-LKM1) 3
• Primary biliary cholangitis (anti-mitochondrial antibodies) 5
• Autoimmune thyroid disease (TPO-Ab, thyroglobulin antibodies) 3
• Primary adrenal insufficiency (21OH-Ab) 3
• Celiac disease (tissue transglutaminase antibodies) 3, 5

Neurologic Autoimmune Diseases

• Autoimmune encephalitis (NMDAR, LGI1, CASPR2, GABA-R antibodies) 3
• Multiple sclerosis 6

Inflammatory Bowel Disease

• Crohn disease 6
• Ulcerative colitis 6

Autoinflammatory Syndromes

• DIRA/DITRA (IL1RN, IL36RN mutations) 1, 4
• PAPA syndrome (PSTPIP1 mutations) 1, 4
• APECED (AIRE mutations, anti-cytokine antibodies) 1, 4
• SAPHO syndrome/CNO 4

When to Refer to Specialists

Refer early to rheumatology if joint swelling (synovitis) is present, symptoms persist despite initial management, or moderate to severe disease is present 1

Refer to immunology when sterile recurrent paronychia occurs with systemic features (fever, arthritis, other skin manifestations) 4

Diagnostic uncertainty, particularly with complex presentations involving rash and migratory arthritis, warrants specialist referral 1