What are the disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis?

Disease-Modifying Antirheumatic Drugs (DMARDs) for Rheumatoid Arthritis

DMARDs are categorized into three main classes: conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), all of which modify the disease process and prevent joint damage in rheumatoid arthritis. 1

Classification of DMARDs

Conventional Synthetic DMARDs (csDMARDs)

• Methotrexate (MTX) is the anchor drug and should be part of the first treatment strategy for RA 1, 2
• Leflunomide is recommended when MTX is contraindicated or not tolerated 1, 2
• Sulfasalazine serves as an alternative first-line option for patients with MTX contraindications 1, 2
• Hydroxychloroquine is used in combination regimens or for milder disease 2, 3
• Azathioprine is available but less commonly used as first-line therapy 3, 4

Biologic DMARDs (bDMARDs)

TNF Inhibitors (the most established biologic class):

• Adalimumab - administered 40 mg subcutaneously every other week 1, 5
• Etanercept - dosed at 50 mg weekly or 25 mg twice weekly 1, 6
• Infliximab - must be combined with MTX (not used as monotherapy) 1, 7
• Golimumab - typically used after inadequate csDMARD response 1, 2
• Certolizumab pegol - dosed 400 mg initially and at weeks 2 and 4, then 200 mg every other week 1, 8

Non-TNF Biologics:

• Abatacept (T-cell costimulation inhibitor) 1
• Rituximab (anti-CD20, B-cell depleting agent) - preferred for patients with previous lymphoproliferative disorder 1, 2
• Tocilizumab (IL-6 receptor inhibitor) - has advantages as monotherapy when csDMARDs cannot be used 1
• Sarilumab (IL-6 receptor inhibitor) 1

Targeted Synthetic DMARDs (tsDMARDs)

• Janus kinase (JAK) inhibitors including tofacitinib, baricitinib, and upadacitinib work intracellularly to block inflammatory signaling pathways 1, 2
• These agents have advantages similar to IL-6 inhibitors when csDMARDs cannot be used as comedication 1

Treatment Algorithm and Strategy

Initial Treatment (DMARD-Naïve Patients)

Start with MTX monotherapy plus short-term glucocorticoids:

• Begin MTX at 7.5-10 mg weekly and rapidly escalate to 20-25 mg weekly within 4-6 weeks 2, 9
• Add low-dose glucocorticoids (≤10 mg/day prednisone equivalent) as bridging therapy, then taper as rapidly as clinically feasible 1, 2
• Always prescribe folic acid supplementation with MTX to reduce side effects 2, 10
• Monitor disease activity every 1-3 months 1, 2

Treatment Escalation Based on Response

If no improvement by 3 months or target not reached by 6 months:

Without poor prognostic factors:

• Switch to or add another csDMARD (leflunomide or sulfasalazine) plus short-term glucocorticoids 1

With poor prognostic factors (high disease activity, RF/anti-CCP positive, early erosions, failure of ≥2 csDMARDs):

• Add a bDMARD or tsDMARD to the csDMARD 1, 2
• TNF inhibitors are typically the first biologic choice 2, 7
• Combine biologics with MTX for optimal efficacy (except IL-6 inhibitors and JAK inhibitors, which can be used without csDMARD comedication) 1

After failure of first bDMARD or tsDMARD:

• Switch to another bDMARD or tsDMARD with a different mechanism of action 1, 8
• Alternatively, a second TNF inhibitor can be tried after first TNF inhibitor failure 1

Critical Monitoring and Safety Considerations

Before initiating biologics:

• Screen for latent tuberculosis and treat if positive before starting TNF inhibitors 7, 5
• Check hepatitis B status; provide prophylactic antiviral therapy when initiating rituximab or other biologics in hepatitis B core antibody positive patients 2

Special population considerations:

• Heart failure (NYHA class III or IV): Use non-TNF inhibitor biologics or tsDMARDs instead of TNF inhibitors 2
• Nontuberculous mycobacterial lung disease: Prefer csDMARDs over biologics; if biologics needed, use abatacept over other options 2
• Previous lymphoproliferative disorder: Rituximab is preferred over other DMARDs 2
• Recent serious infection (within 12 months): Adding/switching to DMARDs is preferred over glucocorticoid escalation 2

Common Pitfalls to Avoid

• Underdosing MTX: Failure to rapidly escalate to 20-25 mg weekly limits efficacy 2, 9
• Omitting folic acid: This leads to unnecessary MTX side effects and discontinuation 2, 10
• Delayed treatment escalation: Waiting beyond 3 months without improvement or 6 months without reaching target allows irreversible joint damage 1, 2
• Using infliximab as monotherapy: Unlike other TNF inhibitors, infliximab must be combined with MTX 7
• Inadequate monitoring: Disease activity must be assessed every 1-3 months during active treatment to guide therapy adjustments 1, 2