What is the best diagnostic approach for a patient presenting with cough, fever, arthritis of the left ankle, and tender red skin lesions, with a normal Complete Blood Count (CBC) and elevated Erythrocyte Sedimentation Rate (ESR)?

Chest X-ray is the Most Important Initial Investigation

The best initial investigation for this patient is a chest X-ray to evaluate for pulmonary sarcoidosis, which classically presents with this exact constellation of findings: cough, fever, ankle arthritis (often asymmetric monoarthritis), erythema nodosum (tender red leg lesions), and elevated ESR with normal CBC 1, 2.

Clinical Syndrome Recognition

This patient presents with Löfgren syndrome, a distinct acute presentation of sarcoidosis characterized by:

• Erythema nodosum (tender red lesions on legs) 1, 2
• Bilateral hilar lymphadenopathy (causing irritable cough) 1
• Arthritis (commonly ankle, often asymmetric) 3, 2
• Fever and constitutional symptoms 1, 2
• Markedly elevated ESR (67 mm/hr indicates moderate elevation, consistent with active inflammation) 1

The normal CBC helps exclude hematologic causes and infectious processes that would typically show leukocytosis 3, 2.

Diagnostic Algorithm

First-Line Investigation

• Chest X-ray is the critical initial test to identify bilateral hilar lymphadenopathy, which is pathognomonic for Löfgren syndrome when combined with erythema nodosum and arthritis 1, 2
• This single test can establish the diagnosis without need for tissue biopsy in classic presentations 1

Essential Baseline Laboratory Panel

While imaging is most important, concurrent laboratory evaluation should include 3, 2:

• Complete blood count with differential (already done, normal)
• Comprehensive metabolic panel including liver enzymes and renal function 2
• Urinalysis 3
• Serum calcium (hypercalcemia occurs in sarcoidosis) 2

Additional Testing Based on Chest X-ray Results

If chest X-ray confirms bilateral hilar lymphadenopathy 1, 2:

• Serum angiotensin-converting enzyme (ACE) level supports diagnosis but is not specific
• Tuberculin skin test or interferon-gamma release assay to exclude tuberculosis
• Tissue biopsy is typically not required in classic Löfgren syndrome with characteristic imaging

If chest X-ray is normal, consider alternative diagnoses 3, 2:

• Rheumatoid factor and anti-CCP antibodies for inflammatory arthritis 3
• Antinuclear antibodies to exclude connective tissue disease 3
• Blood cultures if infectious etiology suspected 2

Why Other Investigations Are Less Appropriate Initially

ESR/CRP Monitoring

• ESR is already elevated at 67 mm/hr, confirming active inflammation 1
• Repeating inflammatory markers without identifying the underlying cause provides no diagnostic value 1, 4
• ESR and CRP lack specificity and cannot differentiate between causes 4, 5

Autoimmune Serologies Without Imaging

• Ordering rheumatologic panels (RF, anti-CCP, ANA) before chest imaging misses the most likely diagnosis 3
• These tests have limited utility when the clinical picture strongly suggests sarcoidosis 3, 6
• Up to 30-40% of inflammatory arthritis patients have negative serologies, making them unreliable as initial screening 6

Joint Aspiration

• While monoarthritis warrants consideration of septic arthritis, the presence of erythema nodosum, fever, and cough points to systemic disease rather than isolated joint infection 3, 7
• Joint aspiration is most indicated when infection is the primary concern 7

Critical Pitfalls to Avoid

• Do not delay chest imaging in patients with this classic triad—missing bilateral hilar lymphadenopathy delays diagnosis and appropriate management 1, 2
• Do not assume elevated ESR always requires extensive autoimmune workup—the clinical context (erythema nodosum + arthritis + respiratory symptoms) should guide investigation 1, 2
• Do not interpret normal CBC as excluding significant disease—sarcoidosis typically presents with normal or only mildly abnormal blood counts 8
• Recognize that ESR of 67 mm/hr is moderately elevated (50-100 mm/hr range) and indicates significant underlying disease requiring prompt diagnosis 1

Prognosis and Management Implications

Löfgren syndrome has an excellent prognosis with spontaneous resolution in most cases 1. Early identification through chest X-ray allows:

• Appropriate counseling about favorable outcomes
• Targeted symptomatic treatment with NSAIDs or short-course corticosteroids 3
• Avoidance of unnecessary immunosuppressive therapy
• Monitoring for the minority who develop chronic sarcoidosis