Is there evidence that low ferritin is associated with disease activity in systemic lupus erythematosus?

Low Ferritin and Lupus: Evidence Summary

Low ferritin is not typically associated with lupus; in fact, the opposite is true—elevated ferritin correlates with disease activity in systemic lupus erythematosus (SLE). 1, 2

Ferritin Patterns in SLE

Elevated Ferritin as a Disease Activity Marker

• Serum ferritin levels in SLE patients correlate positively with disease activity scores (SLEDAI), with patients having SLEDAI ≥11 showing significantly higher ferritin concentrations than those with lower activity scores. 1
• Hyperferritinemia (elevated ferritin) occurs in approximately 18.6% of SLE patients and is associated with more active disease when measured by ECLAM scores (p=0.04). 2
• Ferritin levels decrease significantly after treatment of active lupus, demonstrating its utility as a marker of inflammatory disease burden. 1

Clinical Associations of Elevated Ferritin in SLE

• Hyperferritinemia in SLE is strongly associated with serologic antiphospholipid syndrome, including thrombocytopenia (33.3% vs. 15.4% in normoferritinemic patients, p=0.003), lupus anticoagulant positivity (29.0% vs. 11.3%, p=0.01), and elevated anticardiolipin antibodies. 2
• Ferritin correlates positively with ANA titers, anti-dsDNA antibodies, and SLEDAI scores in lupus patients, reinforcing its role as an acute-phase reactant reflecting disease activity. 3

Low Ferritin in SLE: The Real Story

When Low Ferritin Occurs

• Low ferritin in SLE patients typically indicates true iron deficiency anemia (IDA), not a lupus-specific phenomenon. 4
• Ferritin levels in SLE patients without active inflammation or iron deficiency are generally similar to healthy controls, meaning low ferritin is not a characteristic feature of lupus itself. 3

Diagnostic Challenges: Ferritin as an Acute-Phase Reactant

• Ferritin is an acute-phase reactant that rises during inflammation, potentially masking underlying iron deficiency in SLE patients. 4, 5
• In one study, when soluble transferrin receptor (sTfR) was used to re-classify anemia types, 58% of SLE patients had coexisting iron deficiency anemia and anemia of chronic disease—a group that would be missed by ferritin alone, which initially classified 68% as pure anemia of chronic disease. 4
• Ferritin underestimates iron deficiency in SLE patients because inflammation artificially elevates it, making transferrin saturation <20% and elevated sTfR more reliable markers for detecting true iron deficiency. 4, 5

Anemia Patterns in SLE

Prevalence and Types

• Anemia is the most frequent hematological alteration in SLE, followed by thrombocytopenia. 4
• Iron deficiency anemia is more common than anemia of chronic disease alone in SLE patients, contrary to traditional assumptions. 4
• Autoimmune hemolytic anemia also occurs in SLE and should be evaluated with direct and indirect Coombs testing when anemia is present. 4

Diagnostic Algorithm for Anemia in SLE

• Measure complete blood count, reticulocyte count, serum ferritin, transferrin saturation, and soluble transferrin receptor to accurately classify anemia type in SLE patients. 4
• If ferritin is 30–100 µg/L with transferrin saturation <20% in the setting of active lupus (elevated CRP/ESR), suspect mixed iron deficiency and anemia of chronic disease. 5, 6
• If ferritin is >100 µg/L with transferrin saturation <20% and elevated inflammatory markers, diagnose anemia of chronic disease with functional iron deficiency. 5, 6
• Soluble transferrin receptor >28.1 nmol/L confirms true iron deficiency even when ferritin is elevated by inflammation, as sTfR is not an acute-phase reactant. 4, 5

Critical Clinical Pitfalls

• Do not assume low ferritin is a lupus-specific finding; it indicates iron deficiency that requires investigation for blood loss (gastrointestinal, menstrual) or malabsorption. 4, 5
• Do not rely on ferritin alone to exclude iron deficiency in active SLE; calculate transferrin saturation and consider sTfR when ferritin is 30–100 µg/L with inflammation present. 4, 5
• Do not overlook that ferritin can remain normal or even low during severe lupus flares in some patients, limiting its universal applicability as a disease activity marker. 7
• Recognize that hyperferritinemia in SLE may signal secondary antiphospholipid syndrome, particularly when accompanied by thrombocytopenia or positive lupus anticoagulant. 2

Bottom Line

The evidence shows that elevated—not low—ferritin is associated with lupus disease activity. 1, 2 Low ferritin in SLE patients reflects true iron deficiency, often masked by inflammation, and requires the same diagnostic work-up as in non-lupus patients: investigation for blood loss, malabsorption, and confirmation with transferrin saturation <20% or elevated soluble transferrin receptor. 4, 5