What is the best course of treatment for a female patient with recurrent, purulent large-joint arthritis, positive Antinuclear Antibody (ANA) and Rheumatoid Factor (RF), and improving C-Reactive Protein (CRP) levels on ertapenem, despite negative cultures and no clear autoimmune symptoms?

Treatment Approach for Recurrent Purulent Large-Joint Arthritis with Positive Autoimmune Markers

Complete the current ertapenem course, then transition to methotrexate 15 mg weekly with short-term low-dose prednisone (10-20 mg daily) as bridge therapy, targeting remission or low disease activity while monitoring for treatment response every 4-6 weeks. 1

Diagnostic Reconsideration

This clinical presentation requires immediate diagnostic clarification before committing to long-term immunosuppression. The combination of recurrent purulent arthritis (synovial WBC 50,000-65,000), negative cultures on multiple occasions, positive ANA, RF 45, and improving inflammatory markers on antibiotics creates diagnostic ambiguity between infectious and autoimmune etiologies.

Key Diagnostic Features Suggesting Rheumatoid Arthritis:

• Large joint involvement with high synovial WBC counts can occur in RA, though typically synovial fluid WBC counts range 2,000-50,000/mm³ 1
• RF positivity (45) with positive ANA supports autoimmune disease, though RF has only 70% specificity and can occur in infections 2
• Improving CRP from 20 to 10 on antibiotics could represent either infection resolution or anti-inflammatory effects of antimicrobials 3
• Negative cultures on both admissions despite purulent fluid argues against bacterial arthritis, though culture-negative septic arthritis occurs 1

Critical Differential Diagnoses to Exclude:

Lyme Arthritis must be definitively excluded given the recurrent large-joint involvement and negative cultures 4:

• Order Lyme serology (ELISA with Western blot confirmation) immediately 4
• Lyme arthritis characteristically affects large joints (especially knees) with high synovial WBC counts (10,000-100,000/mm³) and negative cultures 4
• If Lyme serology is positive, treat with doxycycline 100 mg twice daily for 28 days or amoxicillin 500 mg three times daily for 28 days 4

Seronegative Spondyloarthropathy should be considered 1:

• Order HLA-B27 testing given large joint involvement 1
• Examine for psoriatic plaques, nail changes, enthesitis, or inflammatory back pain 1

Amyopathic Dermatomyositis can present with erosive polyarthritis, positive ANA, and negative RF/anti-CCP 5:

• Examine for violaceous erythema over joints, heliotrope rash, Gottron's papules 5
• Order myositis-specific antibodies (anti-Jo-1, anti-Mi-2) and creatine kinase 5
• Consider MRI of proximal muscles if weakness is present 5

Immediate Management Steps

Complete Current Antibiotic Course:

• Finish the ertapenem course as planned for presumed left knee septic arthritis 1
• Monitor CRP weekly during antibiotic therapy to document continued improvement 1

Essential Additional Testing Before Starting DMARDs:

• Synovial fluid PCR for Borrelia burgdorferi if Lyme serology is positive or equivocal 4
• Repeat synovial fluid analysis if any joint re-flares: cell count, Gram stain, culture, crystal analysis 1
• Anti-CCP antibodies (ACPA): High specificity (90%) for RA diagnosis 1
• Complete blood count with differential: Assess for cytopenias before starting methotrexate 1
• Comprehensive metabolic panel: Liver and renal function required before methotrexate 1
• Hepatitis B, Hepatitis C, and tuberculosis screening: Mandatory before any DMARD therapy 1
• Baseline bilateral hand, wrist, and foot X-rays: Document erosions which predict RA diagnosis and persistence 1

Advanced Imaging if Diagnosis Remains Uncertain:

• Ultrasound with Power Doppler of affected joints can detect subclinical synovitis and differentiate inflammatory from non-inflammatory arthritis 1
• MRI with IV contrast is more sensitive for detecting bone marrow edema (osteitis), the best predictor of erosive progression 1

Treatment Algorithm Based on Diagnostic Clarification

If Lyme Arthritis is Confirmed:

• Oral doxycycline 100 mg twice daily for 28 days (first-line) 4
• Alternative: Amoxicillin 500 mg three times daily for 28 days 4
• If persistent arthritis after oral therapy, re-treat with another 4-week oral course or IV ceftriaxone 2 g daily for 2-4 weeks 4
• Avoid intra-articular corticosteroids during antibiotic treatment 4
• If arthritis persists despite IV therapy and synovial PCR is negative, transition to symptomatic treatment with NSAIDs or DMARDs 4

If Rheumatoid Arthritis is Confirmed:

Initiate DMARD Therapy Immediately (do not delay for complete serologic workup) 1:

• Methotrexate 15 mg weekly as first-line DMARD 1

  • Escalate to 20-25 mg weekly if inadequate response after 4-6 weeks 1
  • Add folic acid 1 mg daily to reduce side effects 1

• Short-term low-dose prednisone 10-20 mg daily as bridge therapy while awaiting DMARD effect 1

  • Taper rapidly over 4-8 weeks given osteoporosis risk 1
  • Consider intra-articular glucocorticoid injections for localized joint inflammation 1

• Target remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) 1

Disease Activity Monitoring 1:

• Reassess every 4-6 weeks using SDAI (tender joint count + swollen joint count + patient global + evaluator global + CRP) 1
• Repeat CRP at each visit to monitor inflammatory activity 1
• Repeat hand, wrist, and foot X-rays at 6 and 12 months to monitor radiographic progression 1

Escalation Strategy if Inadequate Response After 3 Months 1:

• Add a biologic agent (TNF inhibitor: adalimumab, etanercept, infliximab) 1
• Alternative: Triple DMARD therapy (methotrexate + hydroxychloroquine + sulfasalazine) 1

If Seronegative Spondyloarthropathy is Confirmed:

• NSAIDs as first-line therapy (indomethacin 25-50 mg three times daily or naproxen 500 mg twice daily) 1
• If inadequate response, consider TNF inhibitor therapy 1
• Physical therapy with emphasis on range of motion and strengthening 1

Critical Pitfalls to Avoid

• Do not start methotrexate or other DMARDs until Lyme disease is definitively excluded 4 - Immunosuppression during active Lyme infection can lead to treatment failure and neurologic complications 4

• Do not dismiss RA diagnosis based on negative cultures alone 1 - Seronegative RA accounts for 20-30% of cases and can present with high synovial WBC counts 1

• Do not delay DMARD therapy waiting for positive serology 1 - Seronegative RA has similar prognosis to seropositive disease and requires early aggressive treatment 1

• Do not use intra-articular corticosteroids during active infection workup 4 - This can worsen septic arthritis or Lyme arthritis 4

• Do not continue antibiotics indefinitely without clear infectious diagnosis 4 - Prolonged antibiotic therapy without documented infection increases complications (DVT, C. difficile, antibiotic resistance) 5

• Monitor for treatment-resistant disease 5 - If arthritis progresses despite appropriate therapy, reconsider diagnosis (dermatomyositis, vasculitis, malignancy-associated arthritis) 5

Prognosis and Long-Term Monitoring

• RF positivity, polyarticular involvement, and elevated CRP predict aggressive disease with high risk of erosive progression 1
• Early treatment prevents irreversible joint damage - outcomes are significantly better when DMARDs are started within 6 weeks of symptom onset 1
• Persistently elevated CRP at diagnosis predicts severe disease with progressive joint erosions and functional deterioration 3
• Regular rheumatology follow-up is essential for treatment optimization and comorbidity screening (cardiovascular disease, osteoporosis, infections) 1