What is the best management approach for a patient with rheumatoid arthritis (RA) and iron deficiency without anemia?

Management of Iron Deficiency Without Anemia in Rheumatoid Arthritis

For RA patients with iron deficiency but no anemia (low ferritin with normal hemoglobin), start oral ferrous sulfate 200 mg once daily with vitamin C 500 mg, continue for 3 months, and reserve investigation for those over 50 years or with high-risk features.

Diagnostic Considerations in RA

The challenge in RA is distinguishing true iron deficiency from inflammation-related ferritin elevation, as ferritin behaves as an acute phase reactant in active disease 1, 2.

Key diagnostic thresholds:

• Ferritin <30 μg/L indicates absolute iron deficiency regardless of inflammation 3
• Ferritin 30-100 μg/L with transferrin saturation <20% suggests combined iron deficiency and anemia of chronic disease 3
• In RA patients with active disease, serum ferritin below 60 μg/L predicts iron-responsive anemia with 83% accuracy 2
• MCV, serum ferritin, and iron saturation together correctly identify iron deficiency in 94% of RA patients, avoiding bone marrow sampling 4

Treatment Approach for Iron Deficiency Without Anemia

First-Line Oral Iron Therapy

Start immediately with:

• Ferrous sulfate 200 mg (65 mg elemental iron) once daily 3
• Add vitamin C (ascorbic acid) 500 mg with each dose to enhance absorption 5, 3
• Take on empty stomach if tolerated; with food if gastrointestinal side effects occur 3

Critical dosing principle: Once-daily dosing is superior to multiple daily doses because hepcidin elevation after iron intake blocks further absorption for 48 hours 3. Never prescribe multiple daily doses 3.

Alternative formulations if ferrous sulfate not tolerated:

• Ferrous gluconate or ferrous fumarate are equally effective 5, 3

Treatment Duration

Continue oral iron for 3 months to replenish stores, even though hemoglobin is already normal 5, 3. This differs from iron deficiency anemia where you continue 3 months after hemoglobin normalizes 3.

Monitoring Protocol

• Check ferritin at 4 weeks to confirm response 3
• Monitor ferritin every 3 months for the first year, then again after another year 5, 3
• Additional iron supplementation if ferritin falls below normal 5

Investigation Strategy

The 2011 British Society of Gastroenterology guidelines provide the most relevant guidance for iron deficiency without anemia 5:

Limited investigation is warranted because:

• The largest study shows very low prevalence of GI malignancy in iron deficiency without anemia: 0.9% in postmenopausal women and men, 0% in premenopausal women 5

Recommended investigation approach:

• All patients: Screen for celiac disease with antiendomysial antibody and IgA measurement 5, 3
• Age >50 years or high-risk features: Consider upper and lower GI investigation after discussing risks and benefits 5
• Age <50 years without risk factors: Treat empirically with oral iron for 3 months and investigate only if iron deficiency recurs within 12 months 5

High-risk features warranting investigation:

• Upper GI symptoms (dyspepsia, dysphagia, early satiety) 5
• Lower GI symptoms (rectal bleeding, change in bowel habits) 5
• Family history of GI malignancy 5
• Unexplained weight loss 5

When to Use Intravenous Iron

Consider IV iron in RA patients with iron deficiency (with or without anemia) if:

• Intolerance to at least two different oral iron preparations 5, 3
• Ferritin levels fail to improve after 4 weeks of compliant oral therapy 3
• Active RA with severe inflammation impairing oral iron absorption 3, 6
• Concurrent inflammatory bowel disease or celiac disease 3

Evidence in RA specifically: A 2012 study demonstrated that IV iron saccharate effectively corrects severe anemia in RA patients without causing disease flares or side effects, with sustained hemoglobin elevation over 1 year 6. While this study focused on anemia, the safety profile supports IV iron use in RA when oral therapy fails 6.

Preferred IV formulations:

• Choose preparations that replace iron deficits in 1-2 infusions rather than multiple infusions 3
• Ferric carboxymaltose (500-1000 mg single doses) can be delivered within 15 minutes 3
• Iron dextran carries higher anaphylaxis risk and requires test doses 3

Special Considerations in RA

Impact of disease activity:

• In clinically active RA, ferritin correlates with disease activity and may not accurately reflect iron stores even when elevated 1
• Serum ferritin falls when disease activity improves with appropriate RA therapy 1
• Consider intensifying RA treatment alongside iron supplementation if disease is active 7

Concurrent causes of anemia in RA:

• Among RA patients with anemia, 45% have iron deficiency, 39% have anemia of chronic disease, 13% have macrocytic anemia, and 3% have other causes 7
• In RA patients with anemia, investigations revealed serious pathology in 20%: established malignancy in 10 patients and premalignancy in 10 patients out of 199 total 7
• This underscores the importance of not assuming all iron abnormalities in RA are benign 7

Critical Pitfalls to Avoid

• Do not assume iron deficiency in RA is always due to chronic disease without measuring ferritin, MCV, and iron saturation 4, 7
• Do not prescribe multiple daily doses of oral iron—this increases side effects without improving efficacy 3
• Do not stop iron therapy prematurely—continue for full 3 months to replenish stores 5, 3
• Do not overlook vitamin C supplementation when oral iron response is suboptimal 5, 3
• Do not delay investigation in patients >50 years or with alarm symptoms, as malignancy prevalence is significant 5, 7
• Do not attribute iron deficiency to RA medications (NSAIDs, aspirin) until GI investigations are completed if indicated 5

Algorithm Summary

1. Confirm iron deficiency: Ferritin <30 μg/L (or <60 μg/L in active RA) with transferrin saturation <20% 3, 4, 2
2. Screen for celiac disease in all patients 5, 3
3. Start oral ferrous sulfate 200 mg once daily with vitamin C 500 mg 3
4. Investigate GI tract if: Age >50 years, alarm symptoms, or high-risk features 5
5. Check ferritin at 4 weeks to confirm response 3
6. Switch to IV iron if: Intolerance to ≥2 oral preparations or no ferritin improvement after 4 weeks 3
7. Continue iron for 3 months total, then monitor every 3 months for 1 year 5, 3
8. Reinvestigate if iron deficiency recurs within 12 months 5