What is seronegative rheumatoid arthritis (RA)?

Seronegative Rheumatoid Arthritis: Definition and Clinical Significance

Seronegative rheumatoid arthritis (SNRA) is rheumatoid arthritis that occurs in the absence of both rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) in serum testing. 1, 2

Core Definition

• SNRA is defined by negative serologic testing for both RF and ACPA, which scores 0 points in the serologic findings category of the 2010 ACR/EULAR classification criteria 1
• This represents approximately 10-20% of all RA cases, though the exact prevalence varies by population 3, 4
• The term "seronegative" is somewhat misleading, as more sensitive testing reveals that many traditionally classified seronegative patients actually harbor autoantibodies when tested with expanded panels 2

Clinical Presentation Patterns

SNRA can manifest in two distinct patterns:

• Oligoarthritis affecting large joints (knees, ankles, shoulders, elbows) 5
• Symmetric polyarthritis of small joints (metacarpophalangeal, proximal interphalangeal, wrists) similar to seropositive disease 5, 6

The clinical presentation is often less severe than seropositive RA, with:

• Less joint deformity (p=0.01) 4
• Less radiographic bone destruction (p=0.04) 4
• Fewer systemic extra-articular manifestations (p=0.02) 4
• Lower overall disease severity (p=0.006) 4

The "Hidden Seropositivity" Phenomenon

When expanded antibody testing is performed, approximately 30-40% of traditionally defined "seronegative" patients actually test positive for other autoantibodies:

• ACPA fine-specificities are found in 30% of anti-CCP2-negative patients 2
• IgA or IgG RF (not routinely tested) appears in 9.4% 2
• Anti-carbamylated protein (anti-CarP) antibodies in 16% 2
• Co-occurrence of at least two types of RA-associated autoantibodies in 9.6% 2

These patients with "hidden" autoantibodies demonstrate clinical features and risk factor associations more similar to seropositive RA, including worse disease outcomes 2

Genetic and Risk Factor Differences

The genetic and environmental risk profile differs substantially from seropositive RA:

• HLA-DRB1 shared epitope (SE) association is present but weaker in SNRA compared to seropositive disease 2, 3
• In anti-CCP2-negative RA, smoking associates with RF presence but not with ACPA 2
• The pathogenic mechanisms appear distinct, suggesting SNRA may represent a different disease endotype 3

Diagnostic Challenges and Clinical Implications

SNRA poses significant diagnostic challenges that can delay treatment:

• Patients score 0 points in the serologic category of ACR/EULAR criteria, requiring higher scores in other domains (joint involvement, acute phase reactants, symptom duration) to reach the diagnostic threshold of ≥6/10 points 1
• The absence of autoantibodies may lead to underdiagnosis and missed "window of opportunity" for early intervention 3
• Ultrasonography should be used to confirm inflammatory synovitis when clinical assessment is uncertain, as recommended for seronegative presentations 5
• Elevated acute phase reactants (CRP or ESR) become more critical for diagnosis, contributing 1 point when abnormal 1

Treatment Response Patterns

SNRA demonstrates distinct therapeutic response patterns:

• Methotrexate 15-25 mg/week remains cornerstone therapy 5
• After inadequate anti-TNF response, seronegative patients respond better to abatacept or tocilizumab rather than rituximab (which targets B-cells and is more effective in seropositive disease) 5, 7
• Triple DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine) is appropriate for moderate to high disease activity 5
• TNF inhibitors remain first-line biologic option with maximum 2 trials before switching mechanism 5

Prognostic Considerations

The presence versus absence of autoantibodies—even when using expanded testing—carries prognostic significance:

• Presence of ACPA fine-specificities or IgA/IgG RF in conventionally defined "seronegative" patients associates with worse clinical outcomes 2
• Truly seronegative patients (negative on all expanded testing) generally have less aggressive disease 4
• Anti-CarP antibodies do not appear to confer the same poor prognosis as ACPA or RF 2