What are the key differential diagnoses and distinguishing features of seronegative YORA (Youth-Onset Rheumatoid Arthritis), RS3PE (Reiter's Syndrome, now known as Reactive Arthritis), and PMR (Polymyalgia Rheumatica)?

Differential Diagnosis of Seronegative YORA, RS3PE, and PMR

RS3PE syndrome, seronegative YORA (young-onset rheumatoid arthritis), and PMR represent distinct but overlapping inflammatory conditions that can be differentiated primarily by age of onset, pattern of joint involvement, presence of hand/foot edema, and response to low-dose corticosteroids.

Tabular Summary of Key Features

Feature	Seronegative YORA	RS3PE Syndrome	PMR
Age of Onset	<50 years [1]	>50 years, peak 70-79 years [2,3]	>50 years, peak 70-79 years [4,3]
Sex Distribution	Female predominance [1]	Male predominance (66-67%) [2,5]	Female predominance [4]
Joint Pattern	MCP + PIP joints (bilateral, symmetric); DIP sparing [1]	MCP (81.5%), PIP (70.4%), wrists (55.5%), shoulders (48%), knees (33.3%), ankles (25.9%) [5]	Bilateral shoulder/hip pain; possible hand/knee swelling [4]
Characteristic Edema	Absent [1]	Bilateral pitting edema of hands/feet (defining feature) [2,6,5,3]	May have distal extremity swelling (12% of cases) [3]
Tenosynovitis	Variable [1]	Present in 100% at inspection; confirmed on MRI [3]	Possible shoulder tenosynovitis [4]
Morning Stiffness	>30-60 minutes [7]	Present, acute onset [2,5]	Acute bilateral shoulder/hip pain with morning stiffness [4]
RF/Anti-CCP	Negative (by definition) [1]	Negative (diagnostic criterion) [2,5]	Negative [4]
ESR/CRP	Elevated [8,7]	Markedly elevated (ESR 62±19 mm/hr, CRP 73±35 mg/L) [2]	Elevated (may be normal in PMR) [4]
Radiographic Erosions	Develop over time [8]	Rare (1/27 patients in one series) [5]	Absent [4]
Response to NSAIDs	Insufficient [7]	Minimal CRP reduction [6]	Insufficient [4]
Corticosteroid Dose	Moderate-high dose DMARD therapy required [7]	Low-dose (10-20 mg prednisone); rapid response [4,2,3]	10-20 mg prednisone daily [4]
Treatment Duration	Chronic, requires DMARDs [7]	Shorter duration (mean 7 months), lower cumulative dose [2,3]	Variable, often prolonged [4]
Relapse Rate	High without DMARDs [7]	Lower frequency [3]	Common, especially with rapid taper [4]
HLA Association	Variable [1]	HLA-B7 (42%) [2]	Not specific [4]

Overlapping Features

Clinical Similarities

• All three conditions affect patients >50 years (except YORA by definition), with peak incidence in the 70-79 age group for RS3PE and PMR 2, 3
• Symmetric polyarthritis is present in all three conditions 1, 2, 5
• Acute onset characterizes both RS3PE and PMR, while YORA may have more gradual progression 7, 2
• Seronegative status (RF and anti-CCP negative) is a defining feature of all three 4, 2, 5
• Elevated inflammatory markers (ESR/CRP) are present in all conditions 4, 8, 2

Diagnostic Challenges

• RS3PE and PMR may coexist: 12% of PMR patients develop distal extremity swelling with pitting edema, suggesting overlap 3
• Demographic similarities: No significant differences in sex, age at onset, acute phase reactants, or HLA-B7 frequency between RS3PE and PMR 3
• Both RS3PE and PMR respond promptly to corticosteroids and neither typically progresses to rheumatoid arthritis 3

Distinguishing Features

Key Differentiators for RS3PE

• Bilateral pitting edema of hands/feet is pathognomonic and present at disease onset in most cases (9/13 in one series) 2, 6, 5
• MRI demonstrates tenosynovitis in 100% of cases and joint synovitis in some patients 3
• Gallium-67 scintigraphy shows symmetric uptake in MCP joints, distinguishing it from PMR 6
• Better prognosis: shorter treatment duration, lower cumulative corticosteroid dose, lower relapse frequency compared to PMR 3
• Minimal CRP reduction with NSAIDs alone (unlike pseudogout or post-infectious arthritis) 6

Key Differentiators for PMR

• Predominant proximal involvement: bilateral shoulder and/or hip pain without significant hand involvement 4
• Absence of pitting edema in most cases (88%) 3
• Giant cell arteritis must be excluded as it occurs in 16-21% of PMR patients 4
• Higher relapse rate and longer treatment duration compared to RS3PE 3
• Baseline ESR >40 mm/hr is associated with higher relapse risk 4

Key Differentiators for Seronegative YORA

• Age <50 years at onset (by definition) 1
• MCP + PIP involvement with DIP sparing is the classic pattern 1
• Progressive erosive disease develops without DMARD therapy 8, 7
• Requires immediate DMARD initiation (methotrexate, biologics) rather than corticosteroids alone 7
• Chronic disease course requiring long-term immunosuppression 7

Critical Diagnostic Pitfalls

Common Misdiagnoses

• Pseudogout mimics all three conditions but shows rapid CRP reduction with NSAIDs and chondrocalcinosis on radiographs 6
• Post-infectious polyarthritis demonstrates prompt CRP reduction with NSAIDs, unlike PMR or RS3PE 6
• Malignancy-associated syndromes: RS3PE has been associated with T-cell lymphoma and myelodysplastic syndrome in some cases 5
• Paraneoplastic RS3PE may occur with checkpoint inhibitor therapy and cannot be distinguished from drug-induced RS3PE 4

Diagnostic Workup Essentials

• Arthrocentesis is mandatory if monoarticular or oligoarticular presentation to exclude septic arthritis and crystal disease 8, 7
• Baseline laboratory assessment must include RF, anti-CCP, ANA, ESR, CRP, complete blood count, creatinine kinase (to exclude myositis), liver function tests, and bone profile 4, 8
• Plain radiographs should be obtained to exclude erosions (suggesting YORA) and chondrocalcinosis (suggesting pseudogout) 8, 6
• Ultrasound or MRI can detect tenosynovitis in RS3PE and differentiate inflammatory from non-inflammatory conditions 8, 3
• Do not start corticosteroids before rheumatology assessment when possible, as this may obscure the diagnosis 4

Treatment Response as Diagnostic Tool

• Prompt response to low-dose corticosteroids (10-20 mg prednisone) within days to weeks supports RS3PE or PMR diagnosis 4, 2, 3
• Lack of improvement with corticosteroids should raise suspicion for malignancy, metastases, or alternative diagnosis 4
• Requirement for DMARD therapy indicates seronegative YORA rather than RS3PE or PMR 7

Special Considerations

RS3PE as a Heterogeneous Syndrome

• RS3PE may not be a distinct entity but rather a manifestation pattern that can occur in multiple conditions including PMR, paraneoplastic syndromes, and drug-induced disease 4, 5
• Hematological malignancies (T-cell lymphoma, myelodysplastic syndrome) have been reported in RS3PE patients, warranting vigilance during follow-up 5

Age-Related Diagnostic Considerations

• In patients <50 years with symmetric polyarthritis and negative serology, seronegative YORA is the primary diagnosis and requires immediate DMARD therapy 7, 1
• In patients >50 years with pitting edema of hands/feet, RS3PE is the leading diagnosis regardless of other joint involvement 2, 5, 3
• In patients >50 years with isolated shoulder/hip pain and no hand edema, PMR is most likely 4