What laboratory tests and treatment approach are recommended for a patient of any age presenting with symptoms of inflammation, such as fever, swelling, or pain, and potentially underlying conditions like arthritis or cancer?

Laboratory Testing for Inflammation

Essential First-Line Inflammatory Markers

For any patient presenting with inflammatory symptoms such as fever, swelling, or pain, order C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as your initial inflammatory markers, with CRP being the preferred test because it is more reliable, not age-dependent, and provides a simple, validated, reproducible result. 1, 2

Core Inflammatory Panel

• CRP is superior to ESR for monitoring inflammation because it responds more rapidly to changes in disease activity and is not influenced by age, gender, or anemia 1, 2
• ESR remains useful for baseline assessment and has particular value in detecting longer-term inflammatory responses (>24 hours), though it should be interpreted alongside CRP 3, 4
• Both markers should be measured at baseline to establish the degree of systemic inflammation and guide treatment intensity 5, 2

When Inflammatory Arthritis is Suspected

If joint swelling, morning stiffness >30 minutes, or pain that improves with NSAIDs (not opioids) is present, immediately expand your workup to include:

• Rheumatoid factor (RF) - 70% specificity, moderate sensitivity 1, 2
• Anti-cyclic citrullinated peptide (anti-CCP) antibodies - 90-95% specificity, 60-70% sensitivity, the most specific test for rheumatoid arthritis 1, 2
• Complete blood count with differential to assess for cytopenias and calculate inflammatory ratios 2
• Comprehensive metabolic panel including liver function, renal function, glucose, and urate levels 2

Order RF and anti-CCP simultaneously at initial presentation - they are complementary tests and both should be obtained together, not sequentially 2

Conditional Autoimmune Testing

When to Add ANA Testing

• Order antinuclear antibodies (ANA) if the diagnosis remains uncertain after initial workup or if symptoms suggest systemic lupus erythematosus or other connective tissue diseases 5, 1, 2
• ANA serves as a screening test but should not delay rheumatology referral if clinical synovitis is present 1, 6

When to Add HLA-B27

• Order HLA-B27 if symptoms suggest reactive arthritis, affect the spine (axial involvement), or if spondyloarthropathy is suspected based on inflammatory back pain 5, 1, 2
• HLA-B27 is superior to ESR for screening ankylosing spondylitis when combined with clinical features of inflammatory back pain 2

Imaging Studies for Inflammatory Arthritis

Initial Imaging

• Obtain bilateral hand, wrist, and foot X-rays at baseline to assess for erosions, which predict rheumatoid arthritis diagnosis and disease persistence 2
• Plain radiographs show periarticular osteopenia, uniform joint space narrowing, and osseous erosions in established disease 2

Advanced Imaging When Diagnosis is Uncertain

• Ultrasound with Power Doppler is superior to clinical examination for detecting subclinical synovitis and can detect inflammation that predicts disease progression even when physical examination is normal 2
• MRI with IV contrast is more sensitive than ultrasound in early stages and detects bone marrow edema (osteitis), which is the best single predictor of future disease progression and functional deterioration 2

Monitoring After Treatment Initiation

Repeat CRP and ESR every 4-6 weeks after starting treatment to monitor disease activity and treatment response 5, 1

• Serial inflammatory markers guide treatment escalation but should not be the sole determinant of treatment decisions 1
• Use composite disease activity measures (SDAI or CDAI) that incorporate inflammatory markers along with clinical assessment 2

Critical Pitfalls to Avoid

Do not dismiss inflammatory arthritis based on normal CRP/ESR - acute phase reactants can be normal even in active inflammatory disease, and seronegative rheumatoid arthritis accounts for 20-30% of cases 1, 2

• Do not wait for positive serology to initiate treatment - early aggressive therapy prevents irreversible joint damage, and seronegative disease has similar prognosis to seropositive disease 1, 2
• Refer to rheumatology within 6 weeks if inflammatory arthritis is suspected, regardless of autoantibody results, as early specialist evaluation improves outcomes and prevents erosive damage 1, 6, 2
• Morning stiffness lasting ≥30 minutes is a hallmark of inflammatory arthritis and requires immediate referral even if inflammatory markers are normal 6

Treatment Approach for Inflammatory Arthritis

Grade 1 (Mild Pain with Inflammation)

• Continue any ongoing cancer therapy if this is immune checkpoint inhibitor-related 5
• Initiate acetaminophen and/or NSAIDs for symptom control 5, 7
• NSAIDs should be used at the lowest effective dose for the shortest duration due to cardiovascular and gastrointestinal risks 7

Grade 2 (Moderate Pain Limiting Instrumental Activities)

• Hold immune checkpoint inhibitors if applicable and resume upon symptom control on prednisone ≤10 mg/day 5
• Escalate to higher-dose NSAIDs if inadequately controlled with initial therapy 5
• Initiate prednisone 10-20 mg/day if NSAIDs are insufficient, with a 4-6 week trial 5
• Consider intra-articular corticosteroid injections for large joints 5
• Refer to rheumatology if joint swelling (synovitis) is present or symptoms persist >4 weeks 5, 6

Grade 3-4 (Severe Pain, Irreversible Damage, or Disabling)

• Hold immune checkpoint inhibitors temporarily and may resume only in consultation with rheumatology if recovery to Grade 1 or less 5
• Initiate oral prednisone 0.5-1 mg/kg immediately 5
• Consider disease-modifying antirheumatic drugs (DMARDs) if no improvement after 4 weeks or if unable to taper corticosteroids below 10 mg/day after 3 months 5
• Synthetic DMARDs include methotrexate and leflunomide 5
• Biologic DMARDs include TNF-α or IL-6 receptor inhibitors (note: IL-6 inhibition can cause intestinal perforation and should not be used in patients with colitis) 5

Special Considerations for Cancer Patients

Early recognition is critical in patients on immune checkpoint inhibitors to avoid erosive joint damage, and corticosteroid-sparing agents should be considered earlier than with other immune-related adverse events due to likely prolonged treatment requirements 5

• Sudden onset polyarthritis can be a paraneoplastic syndrome from malignancy, particularly non-small cell lung cancer, and should prompt evaluation for underlying cancer if no other cause is identified 8
• Consider PCP prophylaxis for patients treated with high-dose corticosteroids for >12 weeks 5