How to differentiate between sepsis and Rheumatoid Arthritis (RA) flare?

Differentiating Sepsis from RA Flare

Use procalcitonin (PCT) ≥1.5 ng/mL and presepsin testing as your primary biomarkers to distinguish sepsis from RA flare, as these markers remain elevated in bacterial infection but stay low in inflammatory flares, while traditional markers like CRP and ESR are unreliable for this distinction. 1, 2

Biomarker-Based Differentiation Algorithm

First-Line Biomarkers (Order Immediately)

Procalcitonin (PCT):

• PCT ≥1.5 ng/mL indicates sepsis with 100% sensitivity and 72% specificity 2
• PCT 0.5-2.0 ng/mL suggests systemic inflammatory response (could be either) 2
• PCT <0.5 ng/mL makes sepsis unlikely 2
• Critical advantage: PCT does NOT elevate in chronic inflammatory states like RA flares, making it specific for acute bacterial infection 2
• PCT rises within 2-3 hours of bacterial exposure and peaks at 6-8 hours 2

Presepsin:

• The American College of Rheumatology and European League Against Rheumatism recommend presepsin specifically for differentiating infection from disease flare in rheumatic patients 1
• Presepsin helps prevent inappropriate escalation of immunosuppressive therapy when infection is present 1
• Interpret presepsin alongside PCT and clinical assessment for optimal accuracy 1

Second-Line Biomarkers

C-Reactive Protein (CRP):

• CRP ≥50 mg/L has 98.5% sensitivity for sepsis 2
• Major limitation: CRP elevates in both sepsis AND RA flares, making it unreliable for differentiation 2
• CRP rises more slowly than PCT and clears more slowly during resolution 2

Clinical Features That Favor Sepsis Over RA Flare

Joint-Specific Findings

Monoarticular involvement strongly suggests septic arthritis:

• Knee and hip are most commonly affected joints in septic arthritis 3
• RA patients have 70 cases/100,000 person-years incidence of septic arthritis versus 2-5/100,000 in general population 4
• Hot, swollen, painful single joint in RA patient should be considered septic until proven otherwise 4

Synovial fluid analysis is mandatory:

• Obtain synovial fluid for cell count, Gram stain, and culture before starting antibiotics 3
• Critical caveat: RA patients with septic arthritis have LOWER synovial fluid leukocyte counts than non-RA patients with septic arthritis due to immunosuppression from steroids and DMARDs 4
• Do not rely on traditional synovial fluid WBC cutoffs in RA patients 4

Systemic Features Favoring Sepsis

Temperature pattern:

• Fever >101.3°F (38.5°C) favors sepsis 5
• RA flares typically cause low-grade fever or no fever

Risk factors for sepsis in RA patients:

• Recent joint surgery or prosthetic joint 3
• Skin infection present 3
• Current use of biologics, JAK inhibitors, or high-dose corticosteroids 6, 4
• Diabetes mellitus (independently associated with sepsis mortality in RA) 7
• Age >80 years 3

Diagnostic Imaging Approach

Initial Imaging

Plain radiographs first:

• Obtain radiographs of affected joint to exclude fracture, tumor, and establish baseline 5
• Soft tissue swelling and joint effusion may be present in both conditions 5

Advanced Imaging When Diagnosis Unclear

Ultrasound for joint aspiration guidance:

• US is highly sensitive for detecting joint effusions 5
• Use image-guided aspiration to ensure safe, accurate needle placement 5
• US can identify periosteal elevation and subperiosteal collections suggesting osteomyelitis 5

MRI if osteomyelitis suspected:

• MRI has 82-100% sensitivity and 75-96% specificity for osteomyelitis 5
• MRI can detect concurrent musculoskeletal infection beyond the joint space 5
• Contrast-enhanced MRI improves detection of abscesses 5

Critical Management Decisions

When to Start Antibiotics

Start empiric antibiotics immediately after obtaining synovial fluid if:

• PCT ≥1.5 ng/mL OR presepsin elevated 1, 2
• Clinical suspicion high (monoarticular hot joint, fever >101.3°F, risk factors present) 3
• Gram stain shows organisms 3

Do NOT withhold antibiotics waiting for culture results if clinical concern exists 3

When to Hold Immunosuppression

The American College of Rheumatology recommends:

• Discontinue biologics, JAK inhibitors, and other immunosuppressants if sepsis diagnosed 5, 6
• Monitor patients closely when transitioning from TNF antagonists to other therapies 6
• Concurrent use of biologics with infection increases serious infection risk from 0.8% to 4.4% 6

Common Pitfalls to Avoid

Do not rely on ESR or CRP alone - both elevate in RA flares and sepsis 2

Do not assume polyarticular involvement excludes sepsis - multifocal septic arthritis can occur, especially in immunosuppressed RA patients 4

Do not wait >6 hours to obtain PCT - early sampling (<6 hours) may produce false-negative results 2

Do not assume normal radiographs exclude infection - early osteomyelitis (<14 days) may show only soft tissue swelling 5

Serial PCT measurements are more predictive than single values - a 50% rise from previous value indicates worsening infection; >25% decrease indicates treatment response 2