What is the likely cause of bilateral hand joint pain in a 33‑year‑old woman with a mildly positive rheumatoid factor, elevated ferritin, and mildly elevated alanine aminotransferase?

Bilateral Hand Joint Pain: Diagnostic Approach

Most Likely Diagnosis

In a 33-year-old woman with bilateral hand joint pain, mildly positive rheumatoid factor, elevated ferritin, and mildly elevated ALT, the primary differential diagnosis is hereditary hemochromatosis (HH) masquerading as rheumatoid arthritis, particularly given the elevated ferritin and liver enzyme abnormalities. 1, 2

Critical Diagnostic Algorithm

Step 1: Assess for True Synovitis

• Perform a detailed joint examination focusing on metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and wrists—look specifically for soft tissue swelling (boggy, warm joints), not just tenderness or bony enlargement. 3
• Apply the MCP squeeze test: compress the MCPs across the hand; pain indicates inflammatory synovitis and supports rheumatoid arthritis (RA). 3
• Document morning stiffness duration: stiffness lasting ≥30 minutes (ideally ≥1 hour) strongly suggests inflammatory arthritis rather than osteoarthritis or hemochromatosis. 3, 4
• Assess symmetry: RA characteristically affects joints symmetrically, while hemochromatosis more commonly targets the 2nd and 3rd MCP joints asymmetrically. 1, 3

Step 2: Interpret the Elevated Ferritin

The combination of elevated ferritin with joint pain mandates immediate evaluation for hemochromatosis, as this condition frequently mimics RA but requires entirely different management. 1, 2

• Order iron studies immediately: serum iron, total iron-binding capacity (TIBC), and transferrin saturation. Transferrin saturation >45% strongly suggests hemochromatosis. 1
• Measure fasting transferrin saturation: this is the most sensitive screening test for HH. 1
• Consider HFE gene testing: if transferrin saturation is elevated, test for C282Y and H63D mutations to confirm hereditary hemochromatosis. 1, 2
• Note the pattern: hemochromatosis arthropathy predominantly affects the 2nd and 3rd MCP joints, wrists, and can involve knees—but typically without true synovitis on examination. 1, 2

Step 3: Complete the RA Serologic Work-Up

• Order anti-CCP antibodies: this test has 90% specificity for RA and is more specific than RF alone; negative anti-CCP with low-positive RF substantially reduces RA probability. 3, 4
• Measure CRP and ESR: markedly elevated inflammatory markers (CRP >10 mg/L, ESR >30 mm/hr) support active inflammatory arthritis, though normal values do not exclude RA. 3, 4
• Recognize RF limitations: RF is positive in only 70% of RA patients, and 5% of healthy individuals have positive RF; furthermore, RF can be mildly elevated in hemochromatosis. 1, 5

Step 4: Obtain Baseline Imaging

• Order bilateral hand and wrist X-rays: look for periarticular osteopenia, uniform joint space narrowing, and marginal erosions (RA) versus hook-like osteophytes at the 2nd and 3rd MCP joints with subchondral cysts (hemochromatosis). 1, 3
• If X-rays are normal but clinical suspicion for RA remains high: obtain ultrasound with Power Doppler to detect subclinical synovitis, which increases diagnostic accuracy by 75% over clinical examination alone. 3

Step 5: Evaluate the Elevated ALT

• Obtain a comprehensive metabolic panel: include liver function tests (AST, ALT, alkaline phosphatase, bilirubin) and assess for hepatic involvement from hemochromatosis. 1, 3
• Screen for viral hepatitis: order hepatitis B and C serology, as chronic viral hepatitis can cause both arthralgia and elevated ferritin. 3
• Consider liver biopsy or MRI: if hemochromatosis is confirmed and liver enzymes remain elevated, quantify hepatic iron overload to assess for cirrhosis risk. 1

Key Differential Diagnoses

Hereditary Hemochromatosis (Most Likely Given Ferritin Elevation)

• Hemochromatosis arthropathy presents with hand joint pain (especially 2nd and 3rd MCPs), elevated ferritin (often >1,000 µg/L), and elevated liver enzymes—but typically without clinical synovitis. 1, 2
• This diagnosis is frequently missed: patients are often misdiagnosed with RA based on joint pain and mildly positive RF, delaying appropriate treatment with phlebotomy. 2
• Treatment is phlebotomy, not DMARDs: if hemochromatosis is confirmed, regular venesection (not methotrexate) resolves symptoms and prevents organ damage. 2

Seronegative Rheumatoid Arthritis

• Seronegative RA accounts for 20-30% of cases and presents with symmetric polyarthritis, morning stiffness >30 minutes, and elevated inflammatory markers despite negative RF and anti-CCP. 3, 4
• Clinical synovitis is mandatory: the 2010 ACR/EULAR criteria require at least one joint with definite swelling not explained by another disease. 3, 4
• If true synovitis is present: calculate the 2010 ACR/EULAR score (≥6/10 points confirms RA) based on joint involvement, serology, acute-phase reactants, and symptom duration. 3

Adult-Onset Still's Disease (AOSD)

• AOSD should be considered if the patient has high-spiking fevers (>39°C, quotidian pattern), salmon-pink evanescent rash, and markedly elevated ferritin (typically >1,000 ng/mL, often >5,000 ng/mL). 1
• Arthritis in AOSD affects knees, wrists, and ankles more than small hand joints, and is often accompanied by sore throat, lymphadenopathy, and hepatosplenomegaly. 1
• Ferritin >1,000 ng/mL with systemic symptoms strongly favors AOSD over RA. 1

Psoriatic Arthritis

• Examine skin and nails carefully: look for psoriatic plaques (scalp, elbows, knees, gluteal cleft), nail pitting, onycholysis, or dactylitis ("sausage digits"). 1, 3
• Psoriatic arthritis can be anti-CCP negative and present with polyarticular involvement and elevated CRP, mimicking RA. 3
• Distal interphalangeal (DIP) joint involvement is more characteristic of psoriatic arthritis than RA, which typically spares DIPs. 1, 3

Management Plan Based on Findings

If Hemochromatosis is Confirmed (Transferrin Saturation >45%, HFE Mutation Positive)

• Refer to hematology immediately for therapeutic phlebotomy (500 mL weekly until ferritin <50 µg/L, then maintenance every 2-3 months). 2
• Do NOT start methotrexate or other DMARDs: these are ineffective for hemochromatosis arthropathy and carry unnecessary toxicity. 2
• Monitor liver function: repeat ALT and consider hepatology referral if cirrhosis is suspected. 1

If Rheumatoid Arthritis is Confirmed (Clinical Synovitis + ACR/EULAR Score ≥6)

• Start methotrexate 15 mg weekly immediately as first-line DMARD, with plan to escalate to 20-25 mg weekly if needed. 3, 6, 4
• Add short-term prednisone 10-20 mg daily as bridge therapy for 2-4 weeks while awaiting methotrexate effect, then taper. 3, 6
• Prescribe folic acid 1 mg daily to reduce methotrexate toxicity. 3
• Reassess at 6-8 weeks: measure disease activity using SDAI or CDAI; target remission (SDAI ≤3.3) or low disease activity (SDAI ≤11). 3, 6
• If inadequate response at 3 months: add triple DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine) or a biologic agent (TNF inhibitor, abatacept). 3, 6

If Diagnosis Remains Uncertain (No Definite Synovitis, Equivocal Serology)

• Monitor clinically every 4-6 weeks with repeat inflammatory markers (CRP, ESR) and joint examination. 3
• Consider ultrasound with Power Doppler to detect subclinical synovitis if clinical suspicion remains high. 3
• Repeat hand X-rays at 6 months to assess for interval development of erosions, which predict RA diagnosis and persistence. 3
• Do NOT delay hemochromatosis work-up: even if RA is suspected, complete iron studies to avoid missing treatable iron overload. 1, 2

Critical Pitfalls to Avoid

• Do not diagnose RA based on positive RF alone: RF is present in 5% of healthy individuals and can be mildly elevated in hemochromatosis, viral hepatitis, and other conditions. 1, 5
• Do not dismiss hemochromatosis because ferritin is "only mildly elevated": ferritin >300 µg/L in a premenopausal woman warrants iron studies, as even moderate elevation can indicate significant iron overload. 1, 2
• Do not start DMARDs without confirming true synovitis: joint pain alone (arthralgia) does not justify methotrexate; clinical swelling is mandatory for RA diagnosis. 3, 4, 5
• Do not ignore the elevated ALT: this may indicate hepatic hemochromatosis, viral hepatitis, or methotrexate contraindication—complete hepatic work-up before starting DMARDs. 1, 3