What is the diagnostic approach for identifying the cause of systemic inflammation?

Diagnostic Approach to Systemic Inflammation

Begin by measuring C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and complete blood count (CBC) with differential at the initial evaluation, as these are the core inflammatory markers recommended by EULAR/ACR guidelines for assessing systemic inflammation. 1

Initial Laboratory Workup

Essential First-Line Tests

• CRP and ESR should be measured together as they provide complementary information about inflammatory activity 1, 2
• CBC with differential is essential to evaluate for peripheral neutrophilia, leukocytosis, and other hematologic abnormalities 1, 3
• Serum amyloid A (SAA) should be added when available, as it is a more sensitive marker for certain inflammatory conditions 1, 3
• S100 proteins may be used as additional inflammatory markers where clinically available 1, 3

Additional Routine Laboratory Tests

• Renal function tests to assess kidney involvement and medication safety 1
• Liver function tests to evaluate hepatic inflammation 4
• Urinalysis to monitor for proteinuria and microalbuminuria, which may indicate amyloidosis development 1
• Alkaline phosphatase, calcium, 25-hydroxy-vitamin D, parathyroid hormone, and phosphate to exclude metabolic bone diseases 1

Autoimmune-Specific Testing (When Clinically Indicated)

• Antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (anti-CCP) should be evaluated when autoimmune conditions are suspected 1, 4
• HLA-B27 typing should be considered in patients with axial involvement or inflammatory back pain 1
• Muscle enzymes (creatine kinase) should be measured if muscle inflammation is suspected 4

Clinical Assessment Components

Physical Examination Findings to Document

• Hepatosplenomegaly, lymphadenopathy, and fatigue as indicators of systemic involvement 1
• Skin manifestations including rashes, urticaria-like lesions, or neutrophilic dermatosis 1, 3
• Joint examination for synovitis, erosions, or inflammatory arthritis 4
• Growth parameters in children at each visit 1

Organ-Specific Evaluations When Indicated

• Ophthalmologic examination (slit lamp and retinal evaluation) for patients with suspected autoinflammatory diseases 1
• Audiologic assessment if sensorineural hearing loss is suspected 1, 3
• Neurologic evaluation for aseptic meningitis, increased intracranial pressure, or cognitive impairment 1

Advanced Imaging When Appropriate

• Whole-body MRI should be preferred for mapping clinically silent but radiologically active lesions in conditions like chronic non-bacterial osteitis 1
• [99mTc]Tc-HDP SPECT/CT or PET/CT with bone-seeking radiotracers are reasonable alternatives when MRI is unavailable 1
• Regional imaging of suspected areas should prioritize modalities that assess both activity and structural changes 1

Genetic Testing Algorithm

• Next-generation sequencing (NGS) platforms should be used when autoinflammatory diseases are suspected (CAPS, TRAPS, MKD, DIRA) 1
• Sanger sequencing of targeted genes (NLRP3, TNFRSF1A, MVK, IL1RN) can validate NGS findings or be used when clinical suspicion is strong 1
• Deep sequencing may be needed to detect somatic mutations not identified by standard methods 1
• Genetic testing should proceed even if inflammatory markers are normal during evaluation, as episodic presentations can have periods of lower inflammation 3

Monitoring Strategy

Frequency of Follow-Up Testing

• ESR, CRP, CBC with differential, SAA (where available), and S100 proteins should be checked at each clinical visit 1, 2
• Urinalysis for proteinuria should be performed every 6-12 months to screen for amyloidosis 1
• Follow-up frequency should be tailored to disease severity, with more frequent monitoring (every 4-6 weeks) after treatment initiation 4

Critical Pitfalls to Avoid

• Do not rely on ESR or CRP alone as they lack sensitivity and specificity; always combine with clinical history and physical examination 5, 6
• Be aware of discordance between ESR and CRP, which is common in chronic inflammatory diseases and can be affected by age, sex, renal disease, and biologic therapies 2, 5, 7
• CRP is more sensitive and responds more quickly to changes in inflammation than ESR 7
• Biologic agents targeting specific inflammatory cytokines may disproportionately affect CRP levels 2
• Do not perform routine bone biopsies; reserve them only for cases with inconclusive imaging or suspicion of malignancy/infection 1
• Screen for amyloidosis in patients with longstanding untreated systemic inflammation, as this serious complication develops in up to 25% of certain autoinflammatory conditions 3