What complement studies, beyond C3 (complement component 3) and C4 (complement component 4), are indicated to investigate autoimmune disease and inflammation in a patient with persistently low C3 and C4 levels despite aggressive treatment?

From the Guidelines

To investigate autoimmune disease and inflammation when C3 and C4 levels remain persistently low despite aggressive treatment, I recommend expanding complement studies to include CH50 (total hemolytic complement), alternative pathway function (AH50), and specific complement component assays (C1q, Factor B, Factor H, properdin) as the most recent and highest quality study suggests 1. When evaluating a patient with persistently low C3 and C4 levels, it is crucial to consider the underlying cause of complement consumption. The most recent study from 2023 1 emphasizes the importance of screening for underlying infections or autoimmune diseases in patients with low complement levels.

Key Considerations

• Start with CH50 to assess the classical pathway function, as this can help determine if the low C3/C4 represents true complement consumption or genetic deficiency.
• Measure complement split products (C3d, C4d) to detect active complement activation.
• Consider genetic testing for complement regulatory proteins like C1 inhibitor or membrane cofactor protein if hereditary complement disorders are suspected.
• Testing for complement activation products such as C3a, C5a, and membrane attack complex (C5b-9) can provide valuable information about ongoing complement consumption.

Complement Studies

• CH50 (total hemolytic complement) to assess classical pathway function
• AH50 (alternative pathway function) to assess alternative pathway function
• Specific complement component assays (C1q, Factor B, Factor H, properdin) to identify specific component deficiencies
• Complement activation products (C3a, C5a, membrane attack complex) to detect ongoing complement consumption

Additional Testing

• Serum and urine immunoelectrophoresis and immunofixation to screen for paraproteins
• Serum free light chain analysis to evaluate for monoclonal proteins
• Genetic testing for complement regulatory proteins if hereditary complement disorders are suspected

By expanding complement studies and considering the underlying cause of complement consumption, targeted therapy can be guided, and more precise therapeutic interventions can be implemented rather than simply increasing general immunosuppression, as suggested by the most recent study 1.

From the Research

Complement Studies Beyond C3 and C4

To investigate autoimmune disease and inflammation in a patient with persistently low C3 and C4 levels despite aggressive treatment, several complement studies beyond C3 and C4 can be considered:

• C4 nephritic factors (C4NeFs) testing: This can help identify autoantibodies that recognize C4b2a, the C3 convertase of the classical pathway of complement, which can be present in some patients with C3 glomerulopathy 2.
• Antiphospholipid antibody testing: This can help evaluate the risk of thrombotic outcomes in patients with a history of low C3 and C4 levels, particularly in those with systemic lupus erythematosus (SLE) 3.
• C3 and C4 phenotyping: This can help identify genetic deficiencies in C3 and C4, which can be associated with autoimmune diseases such as SLE and autoimmune chronic active hepatitis 4, 5.
• Testing for other complement components: Such as C5, C6, C7, C8, and C9, which can be involved in the complement pathway and may be affected in patients with autoimmune diseases 6.

Specific Conditions to Consider

Certain conditions may be associated with low C3 and C4 levels, including:

• Systemic lupus erythematosus (SLE): Patients with SLE may have low C3 and C4 levels, particularly those with a history of renal involvement or thrombotic events 3.
• Autoimmune hemolytic anemia (AIHA): Patients with AIHA may have reduced serum C3 levels, and serum C4 levels may be lower in those with certain subtypes of AIHA 6.
• C3 glomerulopathy: This is a group of rare complement-mediated kidney diseases that can be associated with autoantibodies to C3 and C5 convertases, including C4NeFs 2.
• Autoimmune chronic active hepatitis: This condition may be associated with genetically determined low C4 levels, which can be a predisposing factor to the disease 4.