What are the implications of low Complement component 4 (C4) levels?

From the Guidelines

Low complement C4 levels are a significant indicator of an active autoimmune or inflammatory process, and further investigation is necessary to determine the underlying cause and guide treatment. The implications of low Complement component 4 (C4) levels are multifaceted and can be associated with various autoimmune and inflammatory conditions. According to the most recent study 1, low C4 levels can be a sign of active disease, particularly in conditions like Sjögren's syndrome, which is characterized by dry eye and dry mouth associated with systemic immune dysfunction.

Key Considerations

• Low C4 levels can indicate an increased risk of developing lymphoma, especially in patients with Sjögren's syndrome 1.
• The diagnosis and treatment of underlying systemic immune disorders may decrease morbidity and may even be lifesaving.
• Patients with low C4 levels should undergo a comprehensive evaluation, including: + Repeat C4 testing to confirm the low level + Additional complement tests, such as C3 and CH50, to assess overall complement function + Autoimmune workup, including antinuclear antibody (ANA) test, anti-double stranded DNA (anti-dsDNA) antibody, anti-Smith antibody, rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibody + Evaluation for potential underlying conditions, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, mixed connective tissue disease, and hereditary angioedema

Management and Referral

• A thorough physical examination and review of the patient's medical history for symptoms of autoimmune disorders are essential.
• Consider referral to a rheumatologist for specialized evaluation and management, as patients with Sjögren's syndrome, whether they have secondary autoimmune disease or not, should be comanaged with a rheumatologist due to the many possible comorbid systemic conditions 1.
• The management of patients with Sjögren-related dry eye should include symptoms of both discomfort and visual disturbance, as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume 1.

From the Research

Implications of Low Complement Component 4 (C4) Levels

• Low serum complement activity or low protein concentrations of complement C4 have been observed to concur with disease activities of systemic lupus erythematosus (SLE) 2
• Complete deficiencies of complement components C4A and C4B are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds 2
• Heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated 2
• Low C4 levels have been associated with:
  • Hematological, renal and serological abnormalities in SLE patients 3
  • Peripheral neuropathy, cutaneous vasculitis, RF, cryoglobulins and lymphoma in primary Sjogren's syndrome patients 4
  • Digital gangrene in patients with lupus anticoagulant 3
• Low C4 levels can be a marker of morbidity and mortality in patients with primary Sjogren's syndrome 4
• Measurement of C4 activation products may be better suited to avoid false negative results in screening for hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) 5
• The C4c/C4 ratio may be a better diagnostic measure than total antigenic C4 alone in detecting C1-INH-HAE patients 5