What are the differential diagnoses and initial work‑up for a patient with acute monoarthritis?

Acute Monoarthritis: Differential Diagnosis and Initial Work-Up

Immediate Priority: Exclude Septic Arthritis

Septic arthritis must be excluded first through immediate diagnostic joint aspiration, as bacterial infection can cause rapid irreversible joint damage within hours to days if untreated. 1, 2, 3

Key Clinical Features Suggesting Septic Arthritis

• Fever, severe pain, inability to bear weight, and refusal to move the joint are red flags requiring urgent arthrocentesis 2, 3
• Immunocompromised state, diabetes, prosthetic joint, recent joint injection, or IV drug use significantly increase septic arthritis risk 2
• However, absence of fever does not exclude infection—up to 40% of septic arthritis cases are afebrile 2

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Differential Diagnoses by Category

Crystal-Induced Arthropathies

• Gout: Typically affects first metatarsophalangeal joint (podagra), but can involve knee, ankle, or wrist; presents with sudden onset severe pain, erythema, and exquisite tenderness 1, 4, 3
• Pseudogout (CPPD): Most commonly affects knee; associated with older age, prior joint trauma, or metabolic disorders (hyperparathyroidism, hemochromatosis) 1, 4, 3

Infectious Causes

• Bacterial septic arthritis: Most commonly Staphylococcus aureus; requires immediate treatment to prevent joint destruction 1, 2, 3
• Reactive arthritis: Follows gastrointestinal, genitourinary, or respiratory infection by 1-4 weeks; HLA-B27 testing should be considered when clinical features suggest seronegative spondyloarthropathy 5, 6
• Lyme disease, viral arthritis (parvovirus B19, hepatitis B/C), tuberculosis, fungal: Consider based on exposure history and geographic location 2, 4

Inflammatory Rheumatic Diseases

• Early rheumatoid arthritis: Can present as monoarthritis before evolving to polyarticular disease; morning stiffness >30 minutes and palpable synovitis support inflammatory etiology 5, 6
• Seronegative spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis, IBD-associated): Look for inflammatory back pain, enthesitis, dactylitis, nail changes, or family history of psoriasis 7, 5, 8
• Systemic lupus erythematosus: Consider in young women with systemic symptoms (fever, rash, photosensitivity, oral ulcers) and positive ANA 5, 8

Non-Inflammatory Causes

• Activated osteoarthritis: Typically affects weight-bearing joints in older patients; morning stiffness <30 minutes distinguishes from inflammatory arthritis 7, 4, 9
• Trauma: Most common cause in emergency settings; obtain detailed history of injury mechanism 2, 9

Rare but Important Considerations

• Hemarthrosis: Suspect with anticoagulation, hemophilia, or significant trauma; synovial fluid appears bloody 2, 4
• Malignancy: Primary bone tumors, metastases, or leukemia can present as monoarthritis 1, 2
• Sarcoidosis: Can cause osseous involvement with arthritis and elevated inflammatory markers; consider chest X-ray and serum ACE levels 8

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Essential Initial Work-Up

Immediate Diagnostic Joint Aspiration (Arthrocentesis)

Perform arthrocentesis immediately when septic arthritis cannot be excluded clinically—this is the single most important diagnostic test. 1, 2, 3

Synovial Fluid Analysis Must Include:

• Cell count with differential:
  • Non-inflammatory: <2,000 WBC/μL
  • Inflammatory: 2,000-50,000 WBC/μL
  • Septic: Usually >50,000 WBC/μL with >90% neutrophils 1, 3
• Gram stain and culture: Mandatory to identify bacterial pathogens; culture is gold standard but takes 24-48 hours 1, 2, 3
• Crystal analysis with polarized microscopy: Identifies negatively birefringent needle-shaped crystals (gout) or positively birefringent rhomboid crystals (pseudogout) 1, 4, 3

Laboratory Tests

• CBC with differential: Leukocytosis suggests infection 1, 4
• ESR and CRP: Quantify systemic inflammation; elevated in septic arthritis, crystal disease, and inflammatory arthropathies 5, 6, 8
• Serum uric acid: Elevated in gout, but normal levels do not exclude acute gout attack 4, 3
• Blood cultures: If septic arthritis suspected, obtain before antibiotics 2, 3
• RF and anti-CCP antibodies: If inflammatory polyarthritis suspected to evolve; anti-CCP has 90% specificity for RA 5, 6
• ANA with reflex to ENA panel: If systemic autoimmune disease suspected (SLE, mixed connective tissue disease) 5, 8
• HLA-B27: When reactive arthritis or axial spondyloarthropathy suspected 5, 6

Imaging

• Plain radiographs of affected joint: First-line imaging to exclude fracture, detect chondrocalcinosis (pseudogout), identify erosions, or reveal bone lesions 7, 5, 6
• Ultrasound with Power Doppler: 75% more accurate than physical examination for detecting synovitis; useful when diagnosis unclear 6
• MRI: Reserved for suspected osteomyelitis, occult fracture, or early inflammatory arthritis when plain films are normal 5

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Critical Pitfalls to Avoid

• Do not delay arthrocentesis while awaiting laboratory results or imaging if septic arthritis is possible—joint destruction occurs rapidly 1, 2, 3
• Do not rely on fever or elevated WBC to rule in/out septic arthritis—clinical presentation is often atypical, especially in elderly or immunocompromised patients 2
• Do not assume normal ESR/CRP excludes inflammatory arthritis—40-50% of patients with active RA have normal acute phase reactants 8
• Crystals and infection can coexist—finding crystals does not exclude septic arthritis; always send synovial fluid for culture 1, 3
• Do not attribute monoarthritis to "activated osteoarthritis" without excluding inflammatory and infectious causes first, particularly in patients without prior OA history 4, 9
• Refer to rheumatology within 6 weeks if inflammatory arthritis suspected, as early DMARD initiation during the "window of opportunity" prevents irreversible joint damage 5, 8

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Algorithmic Approach

1. History: Onset (acute vs. gradual), trauma, fever, systemic symptoms, prior episodes, sexual/GI/respiratory infections, tick exposure, family history of psoriasis or inflammatory arthritis 2, 4, 9

2. Examination: Palpable synovitis (warm, boggy, swollen joint), positive squeeze test, range of motion, skin changes (rash, psoriasis, tophi), enthesitis, dactylitis 5, 6

3. Immediate arthrocentesis if:

   • Fever or systemic toxicity present 2, 3
   • Risk factors for septic arthritis (prosthetic joint, immunosuppression, diabetes, IV drug use) 2
   • Diagnosis unclear after history/exam 1, 3

4. Synovial fluid analysis guides next steps:

   • Positive Gram stain or culture → Septic arthritis: Start IV antibiotics immediately 2, 3
   • Crystals identified → Gout or pseudogout: Treat with NSAIDs, colchicine, or corticosteroids 1, 4
   • Inflammatory fluid (2,000-50,000 WBC) without crystals or infection → Consider early inflammatory arthritis, reactive arthritis, or seronegative spondyloarthropathy; refer to rheumatology 5, 6
   • Non-inflammatory fluid (<2,000 WBC) → Osteoarthritis or mechanical cause 4, 9

5. Imaging and serology based on clinical suspicion and synovial fluid results 5, 6, 8