What is rheumatoid arthritis and how is it treated?

Rheumatoid Arthritis: Definition and Treatment

Rheumatoid arthritis is the most common autoimmune disease affecting the joints, characterized by symmetric polyarthritis with joint swelling (especially hands and feet), morning stiffness lasting ≥1 hour, and progressive joint destruction that requires immediate aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) to prevent disability and preserve quality of life. 1

What is Rheumatoid Arthritis?

Epidemiology and Demographics

• Prevalence: Affects approximately 1% of the population worldwide, with higher rates in persons of European or Asian ancestry 1
• Age of onset: Typical onset around 55 years, though can develop at any age 1
• Gender disparity: Lifetime risk is 3.6% in women versus 1.7% in men 1
• Age-related prevalence: Increases dramatically with age, affecting approximately 6% of white population over 65 years 1

Clinical Presentation

Inflammatory Symptoms:

• Symmetric polyarthritis with joint swelling, predominantly affecting hands and feet, though any appendicular joint may be involved 1
• Morning stiffness lasting 1 hour or longer 1, 2
• Systemic manifestations including fatigue and low-grade fever 2

Markers of Severe Disease:

• Subcutaneous nodules 1
• Interstitial lung disease 1
• Vasculitis 1
• Inflammatory eye disease 1

Mechanical Symptoms (from joint damage):

• Joint instability and deformity 2
• Limited range of motion not responsive to anti-inflammatory treatment 2
• Pain with weight-bearing or specific movements rather than at rest 2

Disease Impact on Morbidity and Mortality

• Work disability: More than one-third of patients eventually experience work disability; 80% working at 2 years, only 68% at 5 years 1
• Life expectancy: Shortened by 3-5 years, especially in patients with extra-articular disease 1
• Mortality causes: Serious treatment-related adverse effects including infections, tumors, and gastrointestinal toxicity 1

Diagnosis

Classification Criteria

Definite RA requires: 1

• Confirmed presence of synovitis in at least 1 joint
• Absence of alternative diagnosis that better accounts for synovitis
• Score ≥6 in 4 domains:
  • Number and site of involved joints (0-5 points)
  • Serologic abnormality (0-3 points)
  • Elevated acute-phase response (0-1 points)
  • Symptom duration (0-1 points)

Serologic Testing

• Anti-citrullinated protein antibody (ACPA): High specificity (90%), moderate sensitivity (60%) 1
• Rheumatoid factor: Lower specificity (70%), comparable sensitivity to ACPA, increases to 80% with prolonged disease 1
• C-reactive protein (CRP): Most clinically useful biomarker, preferred over ESR because it's simpler, more reliable, and not age-dependent 1

Disease Activity Monitoring

Composite measures must be used regularly: 1

• DAS28 (Disease Activity Score-28): Recommended by EULAR for assessing disease activity and treatment response
• SDAI (Simplified Disease Activity Index) and CDAI (Clinical Disease Activity Index): Provide more stringent definitions, don't require complicated calculations, and CDAI doesn't require acute-phase reactant measurement

Monitoring frequency: 1

• High/moderate disease activity: Monthly measurements
• Sustained low disease activity or remission: Every 3-6 months

Treatment Approach

Treatment Goals and Philosophy

Primary treatment goal: Achieve clinical remission, defined as absence of signs and symptoms of significant inflammatory disease activity. 1

The modern treatment paradigm expects complete abrogation of disease activity and remission or near-remission as the standard treatment goal. 1

Key treatment principles: 1

• Timely intervention and accurate diagnosis reduce disease burden and progression
• Early aggressive therapy prevents joint destruction and disability
• Treatment decisions must be made jointly by patient and rheumatologist 1
• Drug therapy should be adjusted at least every 3 months until target is reached 1
• For established, longstanding disease where remission is not achievable, low disease activity is an acceptable alternative 1

Long-term Treatment Goals

• Prevent joint destruction 1
• Prevent comorbidities of disease and treatment (heart disease, osteoporosis) 1
• Restore quality of life 1
• Preserve independence and ability to perform activities of daily living 1
• Maintain vocational and avocational pursuits 1

Pharmacologic Treatment

First-Line Therapy:

Methotrexate is the standard first-line DMARD and the benchmark by which all other therapies are measured. 3, 4, 5

• Indication: Management of severe, active RA in patients with insufficient response to or intolerance of first-line therapy including NSAIDs 3
• Use: Can be used alone or with other non-biologic DMARDs 3
• Dosing: Effective doses (oral or subcutaneous) with folic acid supplementation 5
• Timing: Should be started within 3 months of diagnosis 4
• Concomitant therapy: NSAIDs, low-dose steroids, aspirin may be continued, though possibility of increased toxicity with NSAIDs has not been fully explored 3

Biologic DMARDs:

TNF-α Inhibitors (e.g., Adalimumab/HUMIRA):

• Indication: Reducing signs and symptoms, inducing major clinical response, inhibiting structural damage progression, and improving physical function in moderately to severely active RA 6
• Use: Can be used alone or in combination with methotrexate or other non-biologic DMARDs 6
• Dosing for RA: 40 mg subcutaneously every other week 6
• Alternative dosing: In patients not taking concomitant methotrexate, may increase to 40 mg weekly or 80 mg every other week for additional benefit 6

Critical Safety Warning for Biologic DMARDs: 6

• Serious infections: Increased risk of serious infections leading to hospitalization or death, including active TB (including reactivation of latent TB), invasive fungal infections, and bacterial/viral/opportunistic infections
• Malignancy risk: Lymphoma and other malignancies reported, including fatal cases in children and adolescents
• Hepatosplenic T-cell lymphoma: Rare but fatal, particularly in adolescent/young adult males with IBD receiving concomitant azathioprine or 6-mercaptopurine
• Monitoring requirement: Test for latent TB before and during therapy; initiate treatment for latent TB prior to starting biologic

Other Biologic Options: 7, 8

• TNF-receptor inhibitors
• IL-6 and IL-6R inhibitors
• B cell depleting antibodies (rituximab)
• Inhibitors of co-stimulatory molecules (abatacept)
• IL-1 inhibitors (anakinra)

Targeted Synthetic DMARDs:

• JAK inhibitors (pan-JAK and JAK1/2 inhibitors) 7

Conventional Synthetic DMARDs:

• Hydroxychloroquine, sulfasalazine, leflunomide 7, 8

Treatment Escalation Strategy

Aggressive escalation algorithm: 5

1. Start methotrexate immediately at effective doses with folic acid
2. Monitor disease activity frequently (monthly if high/moderate activity)
3. If methotrexate alone ineffective in controlling RA, rapidly escalate with additional DMARDs
4. Aim for treat-to-target strategy with goal of low disease activity or remission
5. Adjust therapy at least every 3 months until target achieved 1

Adjunctive Therapies

For Inflammatory Symptoms:

• NSAIDs for pain and inflammation control 8
• Glucocorticoids (can be reduced gradually in patients responding to methotrexate) 3, 8

For Mechanical Symptoms: 2

• Thermal modalities (heat or cold) for pain relief
• Joint protection techniques to reduce stress on affected joints
• Activity pacing and energy conservation strategies
• Regular exercise programs (aerobic and resistance training)
• Splinting, orthoses, or bracing for affected joints
• Assistive devices to reduce strain during daily activities
• Rest and physiotherapy as indicated 3

Critical Clinical Pitfalls

Distinguishing inflammatory from mechanical symptoms: 2

• Failing to distinguish between these symptom types leads to inappropriate treatment choices
• Inflammatory symptoms respond to DMARDs; mechanical symptoms require physical interventions
• Mechanical symptoms may not improve with anti-inflammatory therapy alone and require different management approaches
• Focusing solely on inflammatory control without addressing mechanical symptoms leaves patients with unresolved functional limitations

Monitoring failures: 1

• Neglecting regular disease activity assessment leads to suboptimal treatment adjustments
• Must use validated composite measures including joint assessments to guide treatment decisions 1
• Structural changes and functional impairment must be considered in addition to disease activity measures 1

Treatment delays: 1

• Early referral to rheumatologist is critical
• Delayed aggressive treatment results in irreversible joint damage and disability
• The window for preventing long-term disability closes rapidly after disease onset

Combination therapy risks: 3

• Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents has not been fully studied and may increase adverse effects
• Concomitant use of NSAIDs with methotrexate carries potential for increased toxicity that has not been fully explored