Rheumatoid Arthritis: Management in Adults

Pathogenesis (Why This Guides Treatment)

• TNF, IL-1, IL-6 (from macrophages) - recruit leukocytes, activate proteases destroying cartilage
• IL-17 (from Th17 cells) - recruits neutrophils and monocytes
• RANKL (from activated T cells) - stimulates osteoclasts causing bone resorption
• Anti-citrullinated peptide antibodies (ACPA) - present in ~70% of patients; associated with disease severity
• Rheumatoid factor (RF) - IgM/IgA autoantibodies binding IgG Fc; present in ~80%

Major processes in RA pathogenesis - Robbins & Kumar Basic Pathology

Diagnosis and Classification

• Joint involvement (large vs. small, number)
• Serology (RF, ACPA - negative, low positive, high positive)
• Acute phase reactants (CRP, ESR)
• Duration (≥6 weeks)

• Symmetric synovitis with morning stiffness >1 hour (hallmark)
• Predilection for MCPs, PIPs, wrists, MTPs
• Extraarticular: rheumatoid nodules, pulmonary fibrosis, vasculitis, sicca, pericarditis
• Poor prognostic factors: functional limitation, extraarticular disease, RF/ACPA positivity, bony erosions on imaging

Treatment Philosophy: Treat-to-Target (T2T)

Target = sustained clinical remission (or low disease activity in long-standing/refractory disease). Any disease activity above low disease activity is unacceptable.

• Monitor disease activity every 1-3 months when active
• If no improvement at 3 months after starting treatment, or target not reached at 6 months - adjust therapy
• Once target is sustained, monitoring frequency can decrease

Pharmacological Management

Step 1: Start DMARDs at Diagnosis

Conventional Synthetic DMARDs (csDMARDs)

Glucocorticoids

• Short-term use at the start of therapy (alongside MTX) is recommended by EULAR 2025 to bridge until DMARDs take effect
• Low-dose prednisone ≤10 mg/day or intraarticular injections for flares
• Not for long-term monotherapy; taper and discontinue once DMARD is effective
• Risks: osteoporosis, hyperglycemia, infection - co-prescribe calcium/vitamin D and consider bisphosphonate

Step 2: Insufficient Response to csDMARDs (3-6 Months)

Biological DMARDs (bDMARDs)

Targeted Synthetic DMARDs (tsDMARDs) - JAK Inhibitors

• Increased risk of major adverse cardiovascular events (MACE) (HR ~1.33 vs. TNFi)
• Increased malignancy risk (HR ~1.48 vs. TNFi, from ORAL Surveillance trial)
• Increased risk of thromboembolism
• Increased all-cause mortality

EULAR 2025 Updated Recommendations (Published March 2026)

1. Start DMARDs as soon as RA is diagnosed
2. Treat-to-target: aim for sustained remission (or low disease activity in refractory/long-standing disease)
3. Monitor every 1-3 months; adjust at 3 months if no improvement, or at 6 months if target not reached
4. MTX (+ short-term glucocorticoids) as first-line; if contraindicated, use leflunomide or sulfasalazine
5. In patients with poor prognostic factors (high disease activity, early erosions, high RF/ACPA), combination csDMARDs or early bDMARD addition is considered
6. If csDMARDs insufficient, add bDMARD or tsDMARD (JAKi with risk consideration)
7. Biosimilars should be used where appropriate (same efficacy as originators)
8. If first bDMARD/JAKi fails, try another (same or different class)
9. In sustained remission: continue DMARDs but dose tapering may be considered; stopping often leads to flares

Non-Pharmacological Management

Monitoring Schedule Summary

Special Populations

• Pregnancy: Stop MTX (teratogenic - category X) and leflunomide (teratogenic) before conception. Hydroxychloroquine and sulfasalazine (+ folic acid) are relatively safer. TNF inhibitors generally compatible in first/second trimester; certolizumab has least placental transfer. JAK inhibitors - avoid.
• Elderly/Renal impairment: Reduce MTX dose; JAK inhibitors also need dose adjustment for renal function.
• Infections/TB: Screen for latent TB (TST or IGRA) before all biologics and JAK inhibitors. Hold immunosuppressives during serious infections.
• Pre-surgery: Decision on holding biologics peri-operatively depends on drug half-life and surgical risk.

• Textbook of Family Medicine, 9th edition (Swanson), p. 879-887
• Goldman-Cecil Medicine International Edition, p. 2811
• Robbins & Kumar Basic Pathology, p. 792
• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set
• EULAR 2025 RA Recommendations (Smolen JS et al., Ann Rheum Dis, 2026) - most current global guideline

Trivial Aortic Regurgitation

What Is It?

Prevalence - More Common Than You Think

• Detected in up to 10-15% of echocardiograms in the general adult population
• Prevalence increases steadily with age
• Found in both normal individuals and those with underlying risk conditions (bicuspid aortic valve, hypertension, connective tissue disease, rheumatic heart disease, prior endocarditis)

Echocardiographic Features

Doppler velocity in the proximal abdominal aorta showing holodiastolic flow reversal (arrows) - indicative of severe AR. Trivial AR has none of this. - Textbook of Clinical Echocardiography

ACC/AHA Staging of Chronic AR

Causes / Associated Conditions

1. Normal individuals (physiological / incidental finding)
2. Aortic valve risk conditions:
   • Bicuspid aortic valve (BAV) - even with no current regurgitation, warrants surveillance
   • Aortic valve sclerosis (age-related thickening without stenosis)
   • Rheumatic heart disease (prior rheumatic fever)
3. Aortic root / ascending aorta conditions:
   • Hypertension-related annular dilation
   • Marfan syndrome / connective tissue disease
   • Dilated aortic sinuses
4. Post-infective: Previous infective endocarditis
5. Inflammatory conditions: Ankylosing spondylitis, systemic lupus erythematosus
   • In ankylosing spondylitis, aortic root inflammation is a well-recognised extraarticular feature; a 2025 study (Bengtsson et al., Clin Rheumatol) followed AR progression in this population

Haemodynamic Significance

• No LV volume overload
• No LV chamber dilation
• No reduction in LV ejection fraction
• No elevated filling pressures
• No symptoms

Clinical Presentation

• No symptoms attributable to trivial AR itself
• Physical examination: may be no audible murmur, or occasionally a very faint early diastolic murmur at the left sternal border
• Pulse pressure: normal (widening of pulse pressure occurs in significant AR)
• No peripheral signs of AR (no Corrigan's pulse, no de Musset's sign, no Quincke's pulsation, no Duroziez's murmur)

Management

Trivial AR in an Otherwise Normal Heart

Surveillance

Endocarditis Prophylaxis

Cardiovascular Risk Factor Management

Natural History and Progression

• Most patients with trivial AR remain stable for many years or decades
• Progression to moderate or severe AR is more likely in those with an underlying structural cause (BAV, dilated aorta, connective tissue disease, rheumatic disease) than in those with isolated trivial AR
• Annual progression rate to severe AR in the broad population of mild AR is approximately 1-2% per year
• Regular clinical review (not necessarily annual echo) is appropriate for isolated trivial AR in an otherwise normal heart

Key Take-Home Points

1. Trivial AR = Stage A in ACC/AHA classification - no hemodynamic burden, no LV changes, no symptoms
2. It is a common incidental finding, present in many normal adults
3. No treatment is needed for trivial AR itself
4. The management priority is identifying and monitoring any underlying cause (BAV, aortic dilation, connective tissue disease)
5. Surveillance echo frequency is dictated by the underlying aetiology, not the trivial AR alone
6. Intervention thresholds apply only to severe AR - trivial AR is far from any surgical indication

• Textbook of Clinical Echocardiography (Otto CM), Chapter 12 - Valvular Regurgitation, pp. 379-413
• Braunwald's Heart Disease, 2-Volume Set, Chapter on Valvular Heart Disease in Older Adults, p. 2755
• ACC/AHA Stages of Chronic AR (Table 12.5, Otto)
• Tsampasian V et al. "Echocardiographic assessment of aortic regurgitation: a narrative review." Echo Res Pract, 2024 [PMID: 38167345]
• 2025 ESC/EACTS Guidelines for management of valvular heart disease (Praz et al.)