What is the prevalence of normal Immunoglobulin G (IgG) levels with abnormal IgG subclasses in patients with Inflammatory Bowel Disease (IBD)?

Prevalence of Normal Total IgG with Abnormal IgG Subclasses in IBD

The occurrence of normal total IgG levels with abnormal IgG subclasses is common in IBD patients, with approximately 20% demonstrating IgG4 subclass deficiency alone while maintaining normal total IgG, and additional patients showing elevations in specific subclasses (particularly IgG1 in ulcerative colitis and IgG2 in Crohn's disease) that may not alter total IgG levels. 1, 2, 3

Specific Prevalence Data

IgG Subclass Deficiency with Normal Total IgG

• IgG4 deficiency occurs in approximately 20% of IBD patients in referral populations, and this deficiency is typically isolated without other antibody deficiencies, meaning total IgG levels often remain normal. 1

• Among 136 IBD patients who had immunoglobulin testing, 57.4% had low IgG or IgG1 levels, though this study did not specifically separate those with isolated subclass deficiency from those with low total IgG. 4

• The general immunology literature indicates that approximately 2.5% of healthy individuals naturally have levels below the normal range for at least one IgG subclass, but this baseline rate is clearly exceeded in IBD populations. 5

Pattern of Subclass Alterations in IBD

Ulcerative colitis patients characteristically show:

• Significantly elevated IgG1 levels (mean 7924 μg/ml vs. control 5173 μg/ml, p<0.05) while maintaining normal IgG2 levels. 3
• Significantly higher IgG4 levels compared to Crohn's disease patients (0.39 vs. 0.29 mg/ml, p<0.05). 2
• These elevations in specific subclasses may occur while total IgG remains within normal range, particularly when IgG2 and IgG3 are not elevated. 2, 3

Crohn's disease patients characteristically show:

• Significantly elevated IgG2 levels (mean 5111 μg/ml vs. control 2477 μg/ml, p<0.05) with near-normal IgG1 levels. 3
• IgG4 deficiency in a substantial subset (20% in referral populations). 1
• The elevation in IgG2 may not always raise total IgG above normal limits, as IgG2 comprises only about 20-30% of total IgG. 3

Clinical Significance of This Pattern

Impact on Disease Severity

IgG4 deficiency specifically (with or without low total IgG) associates with:

• More years requiring biologic therapy (p=0.002) and corticosteroids (p=0.049). 1
• Increased hospital admissions (p<0.001) and clinic visits (p=0.010). 1
• More outpatient antibiotic prescriptions (p<0.001) and CD-related surgeries (p=0.011). 1
• In Crohn's disease specifically, low IgG/IgG1 levels showed hazard ratio of 4.42 for IBD-related surgery (95% CI 1.02-19.23, p=0.048). 4

Correlation with Disease Activity

• IgG3 levels show negative correlation with disease activity indices in ulcerative colitis (p<0.01). 2
• IgG1 (p<0.001) and IgG2 (p<0.001) show positive correlation with disease activity in Crohn's disease. 2
• These correlations can occur independently of total IgG changes. 2

Diagnostic Considerations

When to Measure IgG Subclasses in IBD

Consider measuring IgG subclasses when:

• Patients demonstrate recurrent infections despite adequate IBD treatment. 5
• There is unexplained severe or refractory disease course. 1
• Patients require frequent hospitalizations or surgeries. 1
• Small bowel resections are being considered or have occurred (12.8% of those with low IgG/G1 required small bowel resection vs. 1.7% with normal levels, p=0.024). 4

Important Caveats

• Normal total IgG does not exclude clinically significant IgG subclass deficiency, particularly IgG4 deficiency which is distinct from other antibody deficiencies. 5, 1

• IgG1 comprises approximately 60% of total IgG, so isolated IgG1 deficiency usually (but not always) manifests as low total IgG, making it less likely to be missed. 5

• Medication effects must be considered: antiepileptics, gold, penicillamine, hydroxychloroquine, and NSAIDs can cause secondary IgG subclass deficiency. 5

• Abnormal subclass levels should be confirmed with repeat testing at least one month apart before making clinical decisions. 5, 6

Functional Assessment Beyond Subclass Levels

When IgG subclass abnormalities are identified:

• Assess specific antibody responses to pneumococcal polysaccharide vaccine (test at least 6 serotypes from the 23-valent vaccine). 7
• Evaluate protein antigen responses (e.g., tetanus toxoid). 6
• For patients >6 years, protective response is defined as concentration >1.3 mg/mL for >70% of serotypes tested. 7, 6

Therapeutic Implications

For IgG4-deficient IBD patients with severe disease:

• A case series showed that 10 out of 11 IgG4-deficient IBD patients benefited from and continued intravenous immunoglobulin replacement therapy. 1
• Standard IgG replacement dosing is 400 mg/kg every 28 days when indicated, though optimal dosing in IBD has not been established in controlled trials. 5
• IgG replacement should not be initiated based solely on laboratory values without clinical correlation (recurrent infections, quality of life impact, failure of standard therapy). 5