What is the appropriate workup for a 14‑year‑old male with a three‑month history of persistent monoarthritis of the knee?

Workup of Three-Month Monoarthritis of the Knee in a 14-Year-Old Male

Immediate Diagnostic Priorities

Urgent referral to rheumatology is mandatory within 6 weeks of symptom onset, even if acute-phase reactants are normal or rheumatoid factor is negative, because persistent monoarthritis in an adolescent requires exclusion of juvenile idiopathic arthritis (JIA) and other inflammatory conditions that cause irreversible joint damage if untreated. 1

Essential Clinical Assessment

History Elements

• Duration and pattern of morning stiffness (≥30 minutes suggests inflammatory arthritis; ≥1 hour is characteristic of rheumatoid-type disease) 1
• Presence of systemic symptoms including fever (particularly quotidian fevers >39°C suggesting systemic JIA), rash (salmon-pink evanescent rash of Still's disease, or psoriatic lesions), or extra-articular manifestations 2
• Trauma history to exclude post-traumatic causes 1
• Family history of psoriasis, inflammatory bowel disease, or spondyloarthropathies 3

Physical Examination Specifics

• Joint swelling assessment (true synovitis versus bony enlargement) with a positive "squeeze test" suggesting inflammatory arthritis 1
• Examination for enthesitis (Achilles tendon, plantar fascia insertion) because enthesitis-related arthritis is a distinct JIA category common in adolescent males 3
• Skin examination for psoriatic plaques (scalp, umbilicus, gluteal cleft) or nail pitting, as 14.9–19.4% of psoriatic arthritis cases present with joint symptoms before skin manifestations 2
• Spine and sacroiliac joint examination for tenderness or reduced range of motion 3

Laboratory Workup

First-Tier Serologic Tests

• Rheumatoid factor (RF) should be tested in all patients with suspected JIA and synovitis 1
• Anti-cyclic citrullinated peptide (anti-CCP) antibodies should be measured if RF is negative and combination therapy is being considered, as anti-CCP has 90% specificity and 60% sensitivity for inflammatory arthritis 4, 1
• C-reactive protein (CRP) is preferred over ESR because it is simpler, more reliable, and not age-dependent 1
• Complete blood count with differential to assess for leukocytosis (suggesting systemic JIA or infection) and anemia of chronic disease 3

Additional Laboratory Studies

• HLA-B27 testing is appropriate in adolescent males with monoarthritis to evaluate for enthesitis-related arthritis, a JIA category that often presents with lower-extremity monoarthritis and sacroiliitis 3
• Antinuclear antibody (ANA) to screen for systemic lupus erythematosus, particularly if systemic symptoms are present 3

Synovial Fluid Analysis (If Effusion Present)

• Arthrocentesis with cell count, Gram stain, culture, and crystal analysis is essential to exclude septic arthritis (the most serious complication requiring immediate treatment) and crystal arthropathies 3

Imaging Studies

Plain Radiographs

• Anteroposterior and lateral knee radiographs are the initial imaging modality to detect erosive changes, which indicate a high risk of progressive joint damage and mandate aggressive DMARD therapy 4, 1

Advanced Imaging When Clinical Examination Is Uncertain

• Ultrasound with power Doppler can detect synovitis, effusion, and erosions not evident on clinical examination or plain films, and is particularly useful in patients with obesity or when the diagnosis is uncertain 1
• MRI of the knee detects synovitis, bone edema, and early erosions with higher sensitivity than radiographs or ultrasound, and should be considered if the diagnosis remains unclear after initial workup 1
• MRI of the sacroiliac joints is indicated if HLA-B27 is positive or if clinical examination suggests sacroiliitis, as active sacroiliac arthritis defines a separate JIA treatment group 3

Critical Differential Diagnoses to Exclude

Infectious Causes

• Septic arthritis must be ruled out immediately via arthrocentesis if there is any clinical suspicion (fever, acute onset, severe pain, refusal to bear weight) 3
• Lyme arthritis should be considered if the patient resides in or has traveled to endemic areas 3

Crystal Arthropathies

• Gout and pseudogout are rare in adolescents but can occur; synovial fluid crystal analysis is diagnostic 3

Mechanical and Traumatic Causes

• Meniscal tear, osteochondritis dissecans, or patellofemoral syndrome should be considered if history suggests trauma or mechanical symptoms (locking, catching) 1

Malignancy

• Leukemia or bone tumors can present with monoarthritis; unexplained leukocytosis, anemia, or bone pain warrant further investigation 3

Treatment Initiation Based on Diagnosis

If Juvenile Idiopathic Arthritis Is Confirmed

For monoarthritis (≤4 joints total), initial treatment consists of intra-articular glucocorticoid injection followed by NSAIDs; if moderate or high disease activity persists after glucocorticoid injection and an adequate NSAID trial (approximately 1–2 months), methotrexate 15 mg/m² weekly (maximum 25 mg) should be initiated. 3

For enthesitis-related arthritis specifically, sulfasalazine (starting 500 mg twice daily, escalating to 1000 mg twice daily) is recommended following glucocorticoid injection or an adequate NSAID trial if moderate or high disease activity persists, irrespective of poor prognostic features. 3

Treatment Targets and Monitoring

• The therapeutic goal is remission (SDAI ≤3.3 or CDAI ≤2.8) or low disease activity (SDAI ≤11 or CDAI ≤10), assessed every 1–3 months. 3, 4
• If the target is not achieved within 3 months of methotrexate at maximum tolerated dose (or 6 months for low disease activity), a TNF-α inhibitor should be added. 3

Critical Pitfalls to Avoid

• Do not delay rheumatology referral beyond 6 weeks, as early DMARD initiation prevents irreversible joint damage in JIA 3, 1
• Do not exclude inflammatory arthritis based on normal CRP or negative RF, as seronegative JIA is common and urgent specialist evaluation is still required 1, 2
• Do not continue NSAID monotherapy beyond 2 months in patients with active arthritis, as this is inappropriate and permits ongoing joint damage 3
• Do not miss septic arthritis by failing to perform arthrocentesis when clinically indicated; delayed diagnosis increases morbidity and mortality 3