What is the best course of treatment for a patient with leukopenia, thrombocytosis, fluctuating C-Reactive Protein (CRP) levels, lower back and hip pain, stiffness and pain in multiple finger joints, particularly Metacarpophalangeal (MCP) joints?

Suspected Adult-Onset Still's Disease (AOSD) Requiring Urgent Rheumatologic Evaluation and Immunosuppressive Therapy

This clinical presentation—leukopenia (atypical), thrombocytosis, dramatically fluctuating CRP (4.9-89.5), MCP joint involvement, and axial pain—strongly suggests Adult-Onset Still's Disease (AOSD), though the leukopenia is unusual and warrants exclusion of alternative diagnoses including systemic lupus erythematosus (SLE) before initiating treatment.

Critical Diagnostic Considerations

AOSD Features Present in This Case

• Articular manifestations: MCP joint involvement occurs in 35-42% of AOSD patients, with polyarticular symmetric pattern typical 1
• Axial involvement: Hip pain and lower back symptoms can occur in AOSD, though less common than peripheral joint disease 1
• Inflammatory markers: Dramatically fluctuating CRP (4.9-89.5) is characteristic of AOSD disease activity 1
• Thrombocytosis: Reactive thrombocytosis is common in AOSD and correlates with active inflammation 1

The Leukopenia Paradox

The leukopenia in this case is highly atypical for AOSD and represents a critical red flag. AOSD characteristically presents with marked leukocytosis (often >15×10⁹/L in 50% of patients, with 37% having WBC >20×10⁹/L) due to neutrophilia from bone marrow granulocyte hyperplasia 1. This discrepancy mandates urgent evaluation for:

• Systemic lupus erythematosus (SLE): Leukopenia with thrombocytosis, fluctuating CRP, and polyarthritis affecting MCPs strongly suggests SLE as an alternative diagnosis 2, 3
• Hemophagocytic syndrome: Pancytopenia (including leukopenia) in the context of suspected AOSD requires immediate exclusion of this life-threatening complication requiring prompt immunosuppressive treatment 1

Immediate Diagnostic Work-Up Required

Essential Laboratory Tests

• Complete autoimmune panel: ANA, anti-dsDNA, anti-Smith, complement levels (C3, C4) to evaluate for SLE 2
• Antiphospholipid antibodies: To identify thrombotic versus inflammatory mechanisms 2
• Ferritin level with glycosylated fraction: Extremely elevated ferritin (>1000 ng/mL, often 4000-30,000 ng/mL) with glycosylated fraction <20% is highly suggestive of AOSD 1
• Complete blood count with differential: Assess for pancytopenia suggesting hemophagocytic syndrome 1
• Liver function tests: 50-75% of AOSD patients have hepatic abnormalities 1

Imaging Studies

• MRI of sacroiliac joints and spine: To evaluate for inflammatory changes in axial skeleton 1
• Plain radiographs of hands: Look for characteristic carpal and pericapitate abnormalities that differentiate AOSD from rheumatoid arthritis 1

Critical Exclusions

• Infection screening: Elevated CRP with leukopenia raises concern for occult infection; blood cultures and infectious work-up essential before immunosuppression 2, 3
• Bone marrow biopsy: Consider if pancytopenia develops or leukopenia worsens to exclude hematologic malignancy or hemophagocytic syndrome 1

Treatment Algorithm

If AOSD is Confirmed (After Excluding SLE and Infection)

First-Line Therapy:

• High-dose glucocorticoids: Initiate prednisone 0.5-1 mg/kg/day orally, or methylprednisolone 500-1000 mg IV daily for 1-3 days if severe systemic symptoms 2
• Add immunosuppressant immediately for glucocorticoid-sparing effect 2:
  • Methotrexate 15-20 mg weekly (preferred initial choice for AOSD with prominent articular disease) 1
  • Azathioprine 1-2 mg/kg/day (alternative, pregnancy-compatible) 2

Monitoring During Treatment:

• Weekly CBC initially to monitor for worsening leukopenia or development of pancytopenia 2
• CRP/ESR every 2-4 weeks to assess treatment response 1
• Ferritin levels correlate with disease activity and should normalize with remission 1

If SLE is Confirmed Instead

First-Line Therapy for Lupus Cytopenias:

• Moderate-to-high dose glucocorticoids: Methylprednisolone 500-1000 mg IV daily for 1-3 days, followed by prednisone 0.5-1 mg/kg/day 2
• Immunosuppressant selection 2:
  • Mycophenolate mofetil 1000-1500 mg twice daily (potent option, avoid in pregnancy planning)
  • Azathioprine 1-2 mg/kg/day (preferred in reproductive-age women)
  • Cyclosporine 2.5-5 mg/kg/day (least myelotoxic, useful when bone marrow suppression is concern)

For Refractory Cases:

• Rituximab 375 mg/m² weekly × 4 doses or 1000 mg × 2 doses for refractory thrombocytopenia or severe disease 2
• IVIG 1-2 g/kg for life-threatening situations with active bleeding or concurrent infection 2

Critical Pitfalls to Avoid

Do Not Start Immunosuppression Without:

1. Excluding active infection: Significantly elevated CRP with leukopenia is unusual in pure autoimmune disease and suggests infection 2, 3
2. Ruling out hemophagocytic syndrome: Pancytopenia in suspected AOSD is a medical emergency requiring immediate bone marrow evaluation 1
3. Confirming diagnosis: The atypical leukopenia makes SLE more likely than AOSD; misdiagnosis could lead to inappropriate treatment escalation

Monitoring for Complications

• Infection risk: Severe leukopenia (<500 cells/mm³) requires continuous monitoring and may necessitate prophylactic antibiotics 3
• Bone marrow suppression: Immunosuppressants (particularly mycophenolate, azathioprine, methotrexate) can worsen cytopenias 3
• Disease progression: Thrombocytopenia in SLE associates with worse prognosis including renal disease progression 2

Treatment Duration Expectations

• Prolonged therapy required: Treatment is typically lengthy with frequent relapses during glucocorticoid tapering 2
• Steroid-sparing essential: Early addition of immunosuppressants prevents long-term glucocorticoid toxicity 2

The combination of leukopenia with other features makes SLE more probable than AOSD; urgent rheumatologic consultation with comprehensive autoimmune serologies is mandatory before initiating immunosuppressive therapy.