Why can a patient with rheumatoid arthritis have a markedly low ferritin level?

Why Rheumatoid Arthritis Patients Can Have Very Low Ferritin

In rheumatoid arthritis, very low ferritin (<30 µg/L) indicates true iron deficiency, most commonly caused by chronic gastrointestinal blood loss from NSAID use, dietary insufficiency, or malabsorption—not the inflammatory disease itself.

Understanding the Paradox

Rheumatoid arthritis typically elevates ferritin as an acute-phase reactant during active inflammation 1, 2, 3. When a patient with RA presents with markedly low ferritin, this represents a distinct clinical scenario that overrides the inflammatory drive to raise ferritin levels.

The Dual Nature of Ferritin in RA

• During active inflammation, ferritin behaves as an acute-phase reactant and rises independent of actual iron stores, making it an unreliable marker of iron deficiency when disease activity is high 2, 3.
• When ferritin is very low (<30 µg/L), this threshold indicates severe iron depletion that has overwhelmed the inflammatory stimulus, confirming absolute iron deficiency even in the presence of active disease 1, 4, 3.
• In clinically inactive RA, ferritin <30 µg/L reliably diagnoses iron deficiency with high specificity 1, 4.

Primary Causes of Very Low Ferritin in RA

Gastrointestinal Blood Loss

• Chronic NSAID use is the leading cause of occult GI bleeding in RA patients, causing iron loss that exceeds the body's ability to maintain stores 5, 6.
• Even low-dose aspirin or selective COX-2 inhibitors can produce cumulative blood loss sufficient to deplete iron stores over months to years 5.
• Upper and lower endoscopy should be performed in any RA patient with ferritin <30 µg/L to exclude peptic ulcer disease, gastritis, or colonic lesions 1.

Dietary Iron Insufficiency

• RA patients often have reduced dietary intake due to chronic pain, fatigue, medication side effects (nausea from methotrexate), or functional limitations affecting meal preparation 5, 6.
• Vegetarian or vegan diets without adequate iron supplementation can lead to progressive depletion, particularly in menstruating women 6.

Malabsorption

• Concurrent celiac disease or inflammatory bowel disease occurs at higher rates in RA patients and impairs iron absorption 1.
• Proton pump inhibitors, commonly prescribed alongside NSAIDs, reduce gastric acid and impair non-heme iron absorption 1.

Menstrual Blood Loss

• Premenopausal women with RA face dual iron losses from menstruation plus any NSAID-induced GI bleeding 5, 6.
• Iron deficiency is significantly more common in younger female RA patients 6.

Diagnostic Approach

Initial Laboratory Assessment

• Measure transferrin saturation (TSAT) alongside ferritin; a TSAT <20% confirms iron deficiency 1, 6.
• Check complete blood count for microcytic anemia (MCV <80 fL), though anemia may be absent in early iron depletion 1, 6.
• Obtain inflammatory markers (CRP, ESR) to assess disease activity, recognizing that very low ferritin indicates true deficiency regardless of inflammation level 1, 2, 3.
• Measure soluble transferrin receptor (sTfR) if available; elevated sTfR confirms iron deficiency and is not affected by inflammation 6.

Distinguishing True Iron Deficiency from Anemia of Chronic Disease

Parameter	Iron Deficiency	Anemia of Chronic Disease	Mixed Picture
Ferritin	<30 µg/L	>100 µg/L	30-100 µg/L
TSAT	<20%	<20%	<20%
sTfR	Elevated	Normal	Elevated
Inflammation (CRP/ESR)	Any level	Elevated	Elevated

1, 6, 4, 3

Critical Diagnostic Thresholds in RA

• Ferritin <30 µg/L indicates absolute iron deficiency requiring treatment, regardless of disease activity 1, 4, 3.
• Ferritin 30-60 µg/L in anemic RA patients predicts iron-responsive anemia with 83% accuracy 4.
• Ferritin >60 µg/L has poor predictive value (50%) for iron responsiveness and suggests anemia of chronic disease predominates 4.

Management Strategy

Immediate Iron Replacement

• Initiate oral ferrous sulfate 100-200 mg elemental iron daily for at least 3 months to replenish stores 1.
• Target ferritin >100 µg/L and TSAT >20% to ensure adequate repletion 1.
• Consider intravenous iron if oral iron is not tolerated, malabsorption is documented, or hemoglobin fails to rise after 3 months of oral therapy 1.

Address Underlying Causes

• Discontinue or reduce NSAIDs when possible; substitute with acetaminophen or topical agents 5.
• Add proton pump inhibitor if NSAIDs must be continued, though recognize this may further impair iron absorption 1.
• Perform bidirectional endoscopy to identify and treat GI bleeding sources 1.
• Screen for celiac disease with tissue transglutaminase antibodies if malabsorption is suspected 1.

Monitor Response

• Recheck ferritin and TSAT after 3 months of iron supplementation 1.
• Continue iron therapy until ferritin reaches >100 µg/L, not just until hemoglobin normalizes 1.
• Expect hemoglobin rise of 1-2 g/dL within 4-6 weeks if iron deficiency was the primary cause 4, 3.

Common Pitfalls to Avoid

• Do not assume low ferritin is impossible in active RA; severe iron depletion can occur despite ongoing inflammation 2, 3.
• Do not attribute anemia solely to RA when ferritin is <30 µg/L; this level mandates investigation for blood loss 1, 5.
• Do not stop iron supplementation once hemoglobin normalizes; stores must be fully replenished to prevent rapid recurrence 1.
• Do not rely on ferritin alone in patients with active disease; always calculate TSAT to confirm functional iron availability 1, 6.
• Do not overlook GI malignancy in older RA patients with new-onset iron deficiency; endoscopy is mandatory 1.

Special Considerations

Iron Deficiency Prevalence in RA

• 60-64% of RA patients develop iron deficiency at some point during their disease course 5, 6.
• 38% of anemic RA patients have iron depletion, and 40% of these do not respond to oral iron alone, indicating coexistent anemia of chronic disease 5.
• Iron deficiency is more common in younger patients, females, those with lower disease activity, and those not taking sulfasalazine 6.

Overlap with Anemia of Chronic Disease

• 23-40% of RA patients have pure iron deficiency anemia, while 60-77% have anemia of chronic disease or a mixed picture 5.
• Recovery from anemia occurs in 72% of iron-deficient patients after supplementation, compared to only 42% of those with anemia of chronic disease 5.
• Ferritin 30-100 µg/L with elevated CRP/ESR suggests both true iron deficiency and inflammatory iron sequestration coexist 1.