What factors affect immunoglobulin levels?

Factors Affecting Immunoglobulin Levels

Immunoglobulin levels are affected by primary immunodeficiencies, immunosuppressive medications (particularly rituximab and cyclophosphamide), protein loss syndromes, autoimmune diseases, and age-related factors.

Primary Immunodeficiency Disorders

Primary immunodeficiencies represent the most significant intrinsic causes of abnormal immunoglobulin levels:

• Agammaglobulinemia causes very low or undetectable immunoglobulins with absent or severely reduced B cells, typically presenting in the first 2 years of life with recurrent bacterial respiratory infections 1
• Common Variable Immunodeficiency (CVID) produces variable reduction in ≥2 immunoglobulin classes with normal or moderately reduced B-cell numbers, often diagnosed after age 4 years 1, 2
• Selective IgA Deficiency is defined by IgA <7 mg/dL with normal IgG and IgM levels in patients older than 4 years, affecting approximately 1 in 300-700 white individuals 1, 2
• IgG subclass deficiencies can occur with normal total IgG levels but deficiency in one or more subclasses (IgG1-4), though approximately 2.5% of the population will automatically be "deficient" in at least one subclass by statistical definition 1

Immunosuppressive Medications

Rituximab is the most significant pharmacologic cause of hypogammaglobulinemia, with well-documented effects on all immunoglobulin classes:

• Rituximab causes hypogammaglobulinemia in 21% of patients on long-term therapy, with IgG levels falling below 5 g/L 2
• In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), 27% developed low IgA, 58% developed low IgG, and 51% developed low IgM at 6 months after rituximab treatment 3
• IgM levels take longer to return to normal compared to IgG after rituximab therapy, and IgM deficiency persists even after B cell repopulation to normal levels 4
• Prior cyclophosphamide exposure combined with rituximab increases the risk of hypogammaglobulinemia more than rituximab alone 5
• Antiepileptic drugs (phenytoin, carbamazepine, valproic acid, zonisamide) can cause reversible selective IgA deficiency and hypogammaglobulinemia 2

Protein Loss Syndromes

Protein loss through kidneys, gastrointestinal tract, or lymphatic system causes secondary hypogammaglobulinemia:

• Nephrotic syndrome causes hypogammaglobulinemia due to urinary protein loss, diagnosed by 24-hour urine protein, urine protein/creatinine ratio, and urinalysis 2
• Protein-losing enteropathy results in gastrointestinal protein loss with chronic diarrhea, assessed by stool alpha-1 antitrypsin clearance and intestinal imaging 2
• Lymphatic disorders disrupt lymphatic drainage leading to protein loss 2
• A critical distinguishing feature is that albumin and total protein levels will also be low in protein loss syndromes, unlike true immunodeficiency where only immunoglobulins are affected 2

Autoimmune Diseases and Inflammatory Conditions

Autoimmune diseases can cause both elevated and decreased immunoglobulin levels:

• Waldenström macroglobulinemia causes monoclonal IgM elevation, with treatment indicated when IgM levels exceed 60 g/L due to imminent risk of symptomatic hyperviscosity 6
• Systemic lupus erythematosus (SLE) patients show variable immunoglobulin changes after pneumococcal vaccination, with some studies showing IgG and IgA levels decreasing by day 28 post-vaccination, though remaining in normal range 1
• Good syndrome (thymoma-associated immunodeficiency) presents with late-onset combined immunodeficiency phenotype similar to CVID but with thymoma present 2
• High erythrocyte sedimentation rate (ESR), high SLEDAI scores, and active disease correlate with poor immunological responses to vaccination in SLE patients 1

Glucocorticoid Therapy

Corticosteroid use is independently associated with decreased immunoglobulin levels:

• Higher glucocorticoid doses during follow-up are associated with lower immunoglobulin levels in patients receiving rituximab 5
• Prednisolone dosage is statistically associated with low antibody response to pneumococcal vaccination 1
• The combination of glucocorticoids with other immunosuppressants compounds the risk of hypogammaglobulinemia 5

Age-Related Factors

Age affects both baseline immunoglobulin levels and response to immunosuppressive therapy:

• IgG4 is present in very low concentrations in children younger than 10 years, and therefore IgG4 deficiencies should not be diagnosed before age 10 years 1
• Older age correlates with poorer post-immunization antibody titers (r=0.30, p=0.02) 1
• Earlier disease onset in SLE correlates with poorer immunological response (r=0.43, p=0.02) 1

Clinical Monitoring Considerations

Prior to administering intravenous immunoglobulin (IVIG), serum immunoglobulin levels must be measured because patients with selective IgA deficiency may develop anaphylactic reactions, and pre-existing hypergammaglobulinemia may become aggravated leading to hyperviscosity 1

Rituximab can cause a transient increase in serum IgM in 30-80% of patients, which may exacerbate hyperviscosity symptoms but doesn't indicate treatment failure 6

Sustained, very low levels of IgG (<100 mg/dL) or IgM (<20 mg/dL) for prolonged periods are associated with increased risk of recurrent and sometimes life-threatening infectious episodes, while transient depletion appears better tolerated 7