Anti-CCP 48, RF 18, normal uric acid, left big toe and lateral toe swelling

How to read the labs

• Anti-CCP 48: Check the lab's cutoff. For most assays (upper limit of normal about 20), 48 is a positive result, roughly 2 to 3 times the upper limit. It is more specific for RA than RF. Low-titer positives can still be false positives or occur in other conditions (Firestein & Kelley's Textbook of Rheumatology, "Assays for ACPA Detection").
• RF 18: This is normal or borderline for most labs. A person can have anti-CCP-positive RA with a negative RF.
• Normal uric acid does not exclude gout. Serum urate may be normal during an acute attack, and a raised level is not diagnostic either (Rheumatology, 2-Volume Set 2022, "Crystal Arthropathies"). Urate often drops during the flare itself.

Differential diagnosis

1. Gout.
   • It is the classic cause of big toe (first MTP) swelling, which is called podagra (Firestein & Kelley's Textbook of Rheumatology, "Clinical Presentations of Gout").
   • It is suggested by sudden onset, severe pain, redness, marked tenderness and a male patient.
   • A normal urate does not rule it out.
2. Rheumatoid arthritis.
   • It favors the small joints, especially the MTP joints 2 to 5, usually on both sides, with morning stiffness longer than 30 to 60 minutes and swelling for more than 6 weeks.
   • The first MTP joint can be involved, but an isolated acute big toe flare is less typical.
   • If the hands or other joints are also involved and the swelling is persistent and symmetrical, RA becomes more likely.
3. Psoriatic arthritis or other spondyloarthritis (including reactive arthritis).
   • Look for toe dactylitis ("sausage toe"), nail pitting, psoriasis (including scalp and natal cleft), heel pain from enthesitis, and back pain.
   • Anti-CCP can be positive in a minority of psoriatic arthritis patients.
4. Others to exclude: septic arthritis, pseudogout (calcium pyrophosphate disease), osteoarthritis of the first MTP, and trauma or stress fracture.

Workup

• Joint aspiration. If fluid can be obtained from the swollen toe joint, send it for crystals under polarized microscopy, Gram stain and culture, and cell count. This is the key test. Monosodium urate crystals confirm gout even when serum urate is normal.
• Blood tests: ESR, CRP, CBC, creatinine and eGFR, liver enzymes, and a repeat serum uric acid at least 2 weeks after the flare settles. Also check hepatitis B and C and a TB screen if a DMARD is likely, and HLA-B27 if spondyloarthritis is suspected.
• Imaging:
  • X-rays of both feet and hands.
  • Gout shows punched-out erosions with overhanging edges.
  • RA shows marginal erosions and periarticular osteopenia.
  • Psoriatic arthritis shows erosions with new bone formation and "pencil-in-cup" changes.
  • Ultrasound can show a double-contour sign (gout) or synovitis and erosions (RA).
  • Dual-energy CT shows urate deposits.
• Examination: Look at the skin, nails and spine, and count tender and swollen joints in the hands, wrists, knees and feet.
• RA classification (ACR/EULAR 2010): This applies only if at least one joint has definite synovitis that isn't better explained by another condition. A score of 6 or more out of 10 classifies as RA. The score counts the number and size of joints involved, serology (a positive anti-CCP scores 2 if low-positive, 3 if high-positive), raised ESR or CRP, and symptoms lasting 6 weeks or more.

Treatment

• Rest, ice and elevation.
• An NSAID such as naproxen 500 mg twice daily or etoricoxib, with gastroprotection, if there is no kidney, ulcer or cardiac contraindication.
• Colchicine 1 mg then 0.5 mg an hour later, then 0.5 mg once or twice daily. Adjust the dose for kidney disease and interacting drugs.
• Oral prednisolone 30 to 40 mg daily for 3 to 5 days, or a short taper, is an alternative. It is also reasonable if NSAIDs or colchicine aren't suitable. Avoid steroids until septic arthritis is excluded.

• Treat flares as above.
• Start urate-lowering therapy (allopurinol, starting at 100 mg daily and titrating to a serum urate below 6 mg/dL, or febuxostat) if he has recurrent attacks, tophi, erosions or kidney stones.
• Give flare prophylaxis with low-dose colchicine or an NSAID for the first 3 to 6 months.
• Advise limiting alcohol (especially beer), red meat, seafood and sugary drinks.

• Start a DMARD early, ideally within 3 months of symptom onset.
• Methotrexate 7.5 to 15 mg weekly, increased to 20 to 25 mg weekly as tolerated, with folic acid 5 mg weekly. Monitor CBC and liver enzymes.
• A short course of low-dose prednisolone can bridge the first weeks.
• Add or switch to sulfasalazine and hydroxychloroquine (triple therapy), or a biologic or JAK inhibitor, if the disease isn't controlled within 3 to 6 months. Aim for remission or low disease activity.
• A positive anti-CCP at this titer predicts erosive disease, so early treatment matters.

• Methotrexate or leflunomide for peripheral joint disease.
• A TNF inhibitor, IL-17 inhibitor or IL-23 inhibitor if the disease is severe, erosive, or involves dactylitis or enthesitis.

When to see a doctor urgently

• how long the swelling has lasted, and whether it is acute or persistent;
• whether it has come and gone before;
• whether the hands, wrists or other joints are involved;
• whether he has psoriasis or nail changes;
• the lab's reference range for the anti-CCP;
• whether any foot X-ray has been done.

A normal left foot X-ray does not rule out any of the main possibilities

What it changes

• Early disease is more likely than long-standing disease. Tophaceous gout and erosive RA are less likely right now.
• Anti-CCP 48 stays important. A positive anti-CCP predicts later erosions even when the X-ray is normal, so imaging should be repeated in 6 to 12 months.
• Soft-tissue swelling alone can come from acute gout, early RA, dactylitis in psoriatic arthritis or reactive arthritis, or infection.

Next steps to reach a diagnosis

1. Joint or swelling aspiration. If there is a joint effusion, send fluid for crystals, cell count, and Gram stain and culture. Monosodium urate crystals confirm gout even with normal serum uric acid.
2. Musculoskeletal ultrasound. It is more sensitive than X-ray for early disease.
   • A double-contour sign or tophi suggests gout.
   • Synovitis with power Doppler signal, or early erosions, suggests RA.
   • Dactylitis or enthesitis suggests psoriatic arthritis.
3. Dual-energy CT, if available, shows urate deposits non-invasively. MRI of the foot can show early erosions, bone marrow edema and tenosynovitis if the diagnosis stays unclear.
4. Bloods: ESR, CRP, CBC, creatinine, and liver enzymes. Repeat uric acid after the flare settles. Check hepatitis B and C and a TB screen before any DMARD. Add HLA-B27 if back pain or enthesitis is present.
5. X-rays of both hands and both feet. These often show changes before symptoms do.
6. Clinical examination. Look at the hands, wrists and other joints, and count tender and swollen joints. Check the skin, nails and scalp, and the heels and spine. Ask about morning stiffness and whether the swelling is symmetrical.

Treatment now

• Use an NSAID or colchicine for symptom relief, or a short oral prednisolone course if those aren't suitable. Use steroids only once infection is excluded.
• Don't start long-term urate-lowering therapy or a DMARD until aspiration, ultrasound or the clinical pattern points to a diagnosis.
• Refer to a rheumatologist within 2 to 4 weeks. If swelling lasts more than 6 weeks, involves other joints, or the anti-CCP stays positive with raised CRP or ESR, early methotrexate-based DMARD therapy for RA is justified.

Next steps once you have the results

• Crystals found: treat as gout (see the earlier plan).
• Persistent symmetrical small-joint swelling, raised inflammatory markers, ultrasound synovitis: treat as early seropositive RA with a DMARD.
• Skin or nail psoriasis, dactylitis or enthesitis: treat as psoriatic arthritis.

Treatment plan for early seropositive RA (anti-CCP positive, persistent symmetrical small-joint synovitis, raised ESR/CRP)

Step 0: Baseline tests before starting

• CBC, liver enzymes (ALT/AST), creatinine/eGFR, albumin, fasting glucose and lipids.
• Hepatitis B (HBsAg, anti-HBc) and hepatitis C, HIV, and TB screening (IGRA or Mantoux, plus chest X-ray). This is needed for methotrexate and essential before any biologic.
• Chest X-ray as a baseline, since methotrexate can cause lung toxicity.
• Vaccines: influenza, pneumococcal and COVID-19. Give any live vaccines before starting immunosuppression.
• Counseling: avoid alcohol and stop smoking. Smoking worsens anti-CCP-positive RA.

Step 1: Initial therapy (weeks 0 to 12)

Step 2: Add-on medicines to counter side effects

• Fertility: sulfasalazine can reduce sperm count, usually reversibly. Methotrexate and leflunomide need a conception plan, and the usual advice is to stop for about 3 months before trying to conceive. Discuss this early.
• Leflunomide stays in the body for a long time and needs a washout before conception.

Step 3: Monitoring

• Blood tests: CBC, ALT/AST and creatinine every 2 to 4 weeks for the first 3 months, every 8 to 12 weeks until 6 months, then every 12 weeks once stable.
• Disease activity: DAS28 or CDAI, tender and swollen joint counts, ESR/CRP every 1 to 3 months.
• Targets: at least 50% improvement by 3 months, and remission or low disease activity by 6 months.
• Imaging: repeat X-rays of the hands and feet at 6 to 12 months, or earlier if symptoms worsen.

Step 4: If the target isn't reached after 3 to 6 months

1. Triple therapy. Methotrexate + sulfasalazine (500 mg daily, increased weekly to 1 g twice daily; watch for rash, GI upset, low counts, orange urine) + hydroxychloroquine.
2. Biologic DMARD added to methotrexate:
   • A TNF inhibitor such as adalimumab 40 mg every 2 weeks, etanercept 50 mg weekly, certolizumab or golimumab.
   • Alternatives are abatacept, tocilizumab and rituximab.
   • Side effects include infections, TB or hepatitis B reactivation, injection-site reactions, and rarely demyelination or worsening heart failure. Screen for TB and hepatitis B first.
3. JAK inhibitors (tofacitinib 5 mg twice daily, baricitinib, upadacitinib). These are oral. Risks include herpes zoster, raised lipids, blood clots, and cardiovascular and cancer concerns, so they are usually kept for patients who fail other options.

Duration

• DMARD therapy is long-term, usually lifelong. Stopping often leads to relapse.
• Steroids are a bridge only. Aim to stop within about 3 months.
• After 6 to 12 months of sustained remission off steroids, a specialist may cautiously taper the biologic first, then reduce the dose. Methotrexate is generally continued.
• Any taper needs close follow-up for flares.

Other measures

• Physiotherapy and a joint-protection exercise program.
• Check cardiovascular risk factors (blood pressure, lipids), since RA raises that risk.
• Keep bone health in view if steroids are used.
• Treat gout separately if crystals are found in the big toe. The two can coexist.

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