How do you treat an adult patient with borderline Rheumatoid Factor (RF) levels and symptoms suggestive of rheumatoid arthritis (RA)?

Management of Borderline Rheumatoid Factor Levels

Initial Clinical Assessment

Do not initiate DMARD therapy based solely on a borderline RF level—confirm the presence of inflammatory arthritis through clinical examination and additional testing before starting treatment. 1

The presence of inflammatory activity must be established first, as borderline RF alone does not confirm rheumatoid arthritis and may lead to misdiagnosis and inappropriate treatment. 1

Key Diagnostic Steps

Evaluate for true inflammatory arthritis by assessing:

• Joint examination: Look specifically for swollen joints (not just tender joints), particularly in metacarpophalangeal joints, proximal interphalangeal joints, wrists, and metatarsophalangeal joints 1
• Morning stiffness: Duration greater than 30-60 minutes suggests inflammatory disease 2
• Pattern of joint involvement: Symmetric polyarthritis involving small joints is more consistent with RA 1
• Anti-CCP antibodies: Order this test immediately, as it has 90% specificity for RA and when combined with RF improves diagnostic accuracy, especially in early disease 3, 4

If clinical examination is equivocal and composite indices are unclear, use ultrasonography to detect synovitis. 1 US is particularly valuable when there is doubt about inflammatory activity, as it correlates better with true inflammation than clinical assessment alone in difficult cases. 1

Management Algorithm Based on Clinical Findings

If Inflammatory Arthritis IS Confirmed

Start methotrexate 15-25 mg weekly immediately, escalating rapidly to 25-30 mg weekly within a few weeks, plus short-term low-dose glucocorticoids (≤10 mg/day prednisone equivalent) for rapid symptom control. 3

• Add folic acid supplementation with methotrexate 3
• Use glucocorticoids at the lowest dose for the shortest duration (less than 3 months) 3
• Target clinical remission (SDAI ≤3.3 or CDAI ≤2.8) or low disease activity (SDAI ≤11 or CDAI ≤10) 3
• Assess disease activity every 1-3 months and aim for >50% improvement within 3 months 3
• If target not reached by 6 months, escalate to biologic DMARD or JAK inhibitor 3

For patients with poor prognostic factors (erosive disease on imaging, high disease activity), consider combination therapy from the start: methotrexate plus hydroxychloroquine 400 mg daily, with consideration of adding sulfasalazine for complete triple therapy. 3

If Inflammatory Arthritis is NOT Confirmed

Do not escalate DMARD therapy. 1 Instead:

• Investigate alternative diagnoses: Consider crystal arthropathies (gout, pseudogout), polymyalgia rheumatica, psoriatic arthritis, spondyloarthritis, systemic lupus erythematosus, viral arthritis (parvovirus B19, hepatitis B/C), osteoarthritis, or fibromyalgia 1
• Reassess for comorbidities that mimic arthritis: Obesity and fibromyalgia can elevate patient-reported outcomes and tender joint counts without true inflammatory activity 1
• Consider non-pharmacological interventions: Exercise programs, physical therapy, and occupational therapy 1, 3
• Monitor clinically: Reassess at regular intervals, as the 2010 ACR/EULAR criteria can be fulfilled cumulatively over time 1

Critical Pitfalls to Avoid

Do not treat based on RF level alone. Borderline or even positive RF occurs in healthy individuals and patients with non-RA conditions, leading to false-positive results. 5, 2 Approximately 30% of RA patients are RF-negative at presentation, and many people with positive RF never develop RA. 5

Do not delay appropriate treatment if clinical RA is present. Delaying DMARD initiation when inflammatory arthritis is confirmed leads to irreversible joint damage. 3 The presence of symptoms meeting clinical criteria for RA is more important than the RF level itself. 2

Do not over-rely on laboratory results for referral decisions. GPs tend to refer patients with positive RF more readily than those with negative RF, even when clinical symptoms are equally suggestive of RA. 2 Clinical assessment should drive the decision, not the RF result alone.

Recognize that composite disease activity indices may be misleading in certain contexts. Comorbidities like fibromyalgia can elevate tender joint counts and patient global assessments without true inflammation, while obesity can confound interpretation. 1 In these situations, ultrasonography provides more accurate assessment of inflammatory activity. 1

Special Considerations for Borderline RF

When RF is borderline (just above upper limit of normal but ≤3 times ULN), score it as "low positive" in the 2010 ACR/EULAR classification criteria, contributing 2 points toward the diagnostic score of 6 needed for RA classification. 1

High serum RF levels (>3 times ULN) are associated with worse prognosis: higher disease activity, progressive joint destruction, decreased treatment responsiveness to TNF inhibitors, and lower treatment retention rates. 6 However, borderline RF does not carry the same prognostic significance.

For patients with high RF levels who require biologic therapy, consider that certolizumab pegol (a TNF inhibitor without Fc region) may maintain better efficacy than other TNF inhibitors, as high RF can bind and degrade antibody drugs with Fc regions. 6