What is the best course of treatment for a 30-year-old female with recurrent severe joint pain, particularly in hands and feet, with iron deficiency anemia (IDA) and normal autoimmune, inflammatory, and tick panel labs?

Seronegative Inflammatory Arthritis with Iron Deficiency Anemia

This patient requires bidirectional endoscopy to evaluate for gastrointestinal causes of iron deficiency anemia, followed by iron supplementation and empiric trial of NSAIDs for joint pain, with rheumatology referral if symptoms persist despite iron repletion. 1

Immediate Diagnostic Priority: Address the Iron Deficiency Anemia

The presence of iron deficiency anemia (IDA) in a 30-year-old female with joint pain is not coincidental and must be thoroughly investigated before attributing symptoms solely to a rheumatologic condition.

GI Evaluation for IDA

• For premenopausal women with IDA and no GI symptoms, bidirectional endoscopy is a conditional recommendation (moderate quality evidence), particularly when symptoms impact quality of life as in this case 1
• Non-invasive testing for H. pylori and celiac disease should be performed first 1
• The rationale: while menstrual blood loss is common in premenopausal women, the severity of symptoms and 4-month duration warrant exclusion of occult GI pathology 1
• Ferritin <45 ng/mL confirms iron deficiency in the absence of inflammation 1

Iron Replacement Strategy

• Initiate oral ferrous sulfate 200 mg twice daily as first-line therapy 1
• Lower doses may be equally effective and better tolerated if standard dosing causes GI side effects 1
• Continue iron supplementation for 3 months after correction to replenish stores 1
• Monitor hemoglobin at 3-month intervals for 1 year, then annually 1

Joint Pain Management: Seronegative Inflammatory Arthritis

The clinical presentation—symmetric small joint involvement of hands and feet, morning stiffness, pain worse overnight/morning, intermittent swelling and temperature changes—strongly suggests inflammatory arthritis despite negative serologies. 2

Why Seronegative Disease is Likely

• Small joint involvement (MCPs, PIPs, MTPs) scores higher in RA classification criteria, even when RF and anti-CCP are negative 2
• Morning stiffness ≥1 hour reflects significant inflammatory burden during periods of inactivity 2
• Normal inflammatory markers (ESR, CRP) do not exclude inflammatory arthritis—up to 40% of early RA patients have normal acute phase reactants 2
• The 4-month duration of recurrent symptoms distinguishes this from transient reactive arthritis 3

Initial Symptomatic Treatment

Start NSAIDs as first-line therapy for inflammatory joint pain:

• Naproxen 375-500 mg twice daily is effective for reducing joint swelling, morning stiffness, and improving mobility 4
• Onset of pain relief begins within 1 hour, with analgesic effect lasting up to 12 hours 4
• NSAIDs should be used at the lowest effective dose for the shortest duration necessary 4
• Common pitfall: Avoid combining NSAIDs with aspirin, as aspirin increases naproxen excretion and raises adverse event risk 4

Critical Next Steps

Rheumatology referral is warranted when:

• Small joints of hands or feet are affected, even with negative RF and normal inflammatory markers—this is an urgent referral indication 2
• Symptoms persist despite 4-6 weeks of NSAID therapy 1
• Joint swelling (synovitis) is present on examination 1

The IDA-Arthritis Connection

Iron deficiency itself can contribute to or worsen joint symptoms:

• IDA is associated with poor quality of life and may exacerbate fatigue and pain perception 5
• Anemia of inflammation can coexist with true iron deficiency, particularly in inflammatory arthritis 6, 5
• Correcting the anemia may improve overall symptom burden before escalating to disease-modifying therapy 5

Diagnostic Algorithm Moving Forward

1. Week 0-2: Obtain H. pylori and celiac serologies; start oral iron supplementation; initiate NSAID trial 1

2. Week 2-4: If serologies positive, treat accordingly; if negative and symptoms severe, proceed with bidirectional endoscopy 1

3. Week 4-8: Reassess joint symptoms on NSAIDs and monitor hemoglobin response to iron 1

4. Week 8-12: If joint symptoms persist despite iron repletion and adequate NSAID trial, refer to rheumatology for consideration of disease-modifying therapy 1, 2

Important Caveats

• Do not delay iron supplementation waiting for endoscopy—begin treatment immediately 1
• Intravenous iron is not first-line in this patient unless oral iron fails or is not tolerated (IV iron is preferred in IBD, but this patient has no evidence of malabsorption) 1
• Avoid routine biopsies for celiac disease during endoscopy unless serologies are positive or endoscopic abnormalities are present 1
• The absence of autoantibodies does not rule out inflammatory arthritis—seronegative disease accounts for 20-30% of RA cases 2
• Physical activity and exercise have the most uniformly positive effects on pain in inflammatory arthritis and should be encouraged alongside pharmacologic therapy 1