Can a patient with normal Rheumatoid Arthritis (RA) tests, including Sedimentation rate (SED) and Erythrocyte Sedimentation Rate (ESR), still experience Rheumatoid Arthritis symptoms?

Can Patients with Normal RA Lab Tests Still Experience RA Symptoms?

Yes, patients with normal rheumatoid arthritis (RA) lab tests, including normal sedimentation rate (SED) and erythrocyte sedimentation rate (ESR), can still experience RA symptoms, as more than 30-40% of RA patients have normal acute phase reactants despite active disease. 1

Understanding Normal Lab Values in Active RA

Prevalence of Normal Inflammatory Markers

• More than 40% of patients with RA have a normal ESR or CRP despite having active disease 1
• In a large US registry study of 9,135 RA patients with active disease (CDAI >2.8), 58% had neither elevated ESR nor CRP 2
• Only 16% of patients with active RA had both ESR and CRP elevated, while 26% had either ESR or CRP elevated 2

Discordance Between Lab Tests and Clinical Symptoms

• The European League Against Rheumatism (EULAR) guidelines recognize that patients can have "well-controlled disease according to above standards, but still having RA symptoms that are causing a reduction in quality of life" 3
• APR levels often do not correlate with disease activity as measured by joint counts and global assessments 2
• The correlation between ESR/CRP and clinical measures of disease activity is weak in RA patients 4

Clinical Implications

Diagnosis and Assessment

• Essential laboratory tests for RA diagnosis include ESR, CRP, RF, and ACPA, but negative tests do not exclude RA 5
• When evaluating undifferentiated peripheral inflammatory arthritis (UPIA), ESR and CRP should be performed at baseline but may have limited diagnostic and prognostic value 3
• ESR showed some diagnostic value for the development of RA but no prognostic value for persistence or structural damage 3
• CRP appeared to be a poor predictor of persistent arthritis, radiological progression, and functional disability 3

Disease Activity Monitoring

• Composite measures such as SDAI, CDAI, and DAS28 should be used to determine disease activity 5
• The CDAI does not require an acute-phase reactant, making it useful for real-time assessment when lab results are not available 3
• The inclusion of acute-phase reactants in measures like DAS28 and SDAI can complicate assessment, as:
  • ESR contributes 15% of the information in DAS28-ESR
  • Remission may be underestimated in high ESR states with few active joints
  • In low ESR states, remission criteria may be met despite significant swollen joints 3

Clinical Approach for Patients with Normal Labs but RA Symptoms

1. Do not exclude RA diagnosis based solely on normal acute phase reactants

   • Consider the full clinical picture, including joint symptoms and other clinical features 6

2. Perform comprehensive antibody testing

   • Test for both RF and ACPA/anti-CCP, as these have higher diagnostic value than acute phase reactants 5
   • Negative tests do not exclude progression to RA 3

3. Use clinical disease activity measures

   • Rely on CDAI which doesn't require acute phase reactants when ESR/CRP are normal 3
   • Perform detailed joint counts to accurately assess disease activity

4. Consider additional imaging

   • Ultrasound and MRI can detect synovitis even when lab tests are normal 5, 6

5. Monitor for changes over time

   • Obtain both ESR and CRP at initial visits, as discordance is common 2
   • Repeat measurements when clinically relevant 3

Pitfalls to Avoid

• Relying solely on lab tests for diagnosis or treatment decisions

  • Laboratory tests cannot serve as a gold standard for diagnosis and management in all individual RA patients 1

• Dismissing symptoms when labs are normal

  • Morning stiffness, joint tenderness, and swelling can be present despite normal inflammatory markers 6

• Failing to obtain both ESR and CRP

  • These tests can be discordant in 28% of cases 7
  • When discordance occurs, CRP is generally a better measure of disease activity than ESR 7

• Overlooking non-inflammatory components of RA

  • Patients may have predominantly non-inflammatory complaints that still impact quality of life 3

By understanding that normal inflammatory markers do not rule out active RA, clinicians can better diagnose and manage patients whose laboratory findings do not match their clinical presentation.