What are the contraindications to Disease-Modifying Antirheumatic Drugs (DMARDs)?

Contraindications to Disease-Modifying Antirheumatic Drugs (DMARDs)

The primary contraindications to DMARDs include active infections, pregnancy for certain agents, severe hepatic or renal impairment, and specific comorbidities that vary by drug class. Understanding these contraindications is essential for safe prescribing and monitoring of these medications in patients with inflammatory arthritis.

General Contraindications Across DMARD Classes

Absolute Contraindications:

• Active, serious infections - All DMARDs are contraindicated during active serious infections due to their immunosuppressive effects 1
• Known hypersensitivity to the specific agent or its components
• Pregnancy and lactation for certain DMARDs (particularly methotrexate, leflunomide)
• Live vaccines - Concurrent administration with biological DMARDs is contraindicated 2

Relative Contraindications:

• History of recurrent infections
• Untreated latent tuberculosis (particularly for biological DMARDs)
• Demyelinating disorders (for TNF inhibitors)
• Malignancy or history of recent malignancy (particularly for biological DMARDs)

Specific Contraindications by DMARD Type

Conventional Synthetic DMARDs (csDMARDs)

Methotrexate

• Severe hepatic impairment
• Severe renal impairment (GFR <30 ml/min)
• Pregnancy and breastfeeding (pregnancy category X)
• Alcoholism or chronic liver disease
• Pre-existing blood dyscrasias (severe anemia, leukopenia, thrombocytopenia)
• Pulmonary disease (relative contraindication, requires careful assessment) 1

Leflunomide

• Severe hepatic impairment
• Pregnancy (pregnancy category X)
• Severe immunodeficiency
• Severe hypoproteinemia

Sulfasalazine

• Sulfa allergy
• G6PD deficiency
• Intestinal or urinary obstruction
• Porphyria

Hydroxychloroquine

• Pre-existing maculopathy
• G6PD deficiency (relative contraindication)

Biological DMARDs (bDMARDs)

TNF Inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab)

• Moderate to severe heart failure (NYHA class III/IV) 1
• Demyelinating disorders (multiple sclerosis, optic neuritis)
• Active tuberculosis or untreated latent tuberculosis
• Hepatitis B carrier state (relative contraindication, requires antiviral prophylaxis) 1
• History of lymphoma or other malignancy

IL-6 Inhibitors (tocilizumab, sarilumab)

• Severe neutropenia (<500 cells/mm³)
• Severe thrombocytopenia (<50,000 platelets/mm³)
• Elevated liver enzymes (>5× upper limit of normal)
• Active diverticulitis (risk of perforation)

T-Cell Co-stimulation Inhibitor (abatacept)

• Hypersensitivity to abatacept or its components
• Concurrent use with TNF inhibitors (increased infection risk) 1

B-Cell Depleting Therapy (rituximab)

• Hypersensitivity to rituximab
• Active hepatitis B infection
• Severe cardiac disease

Targeted Synthetic DMARDs (tsDMARDs)

JAK Inhibitors (tofacitinib, baricitinib, upadacitinib)

• Severe hepatic impairment
• ALC <500 cells/mm³
• ANC <1000 cells/mm³
• Hemoglobin <8 g/dL
• Active serious infection
• History of venous thromboembolism (relative contraindication) 1
• Age ≥65 with cardiovascular risk factors (relative contraindication) 1

Special Considerations

Pregnancy and Breastfeeding

• Contraindicated during pregnancy: Methotrexate, leflunomide, cyclophosphamide
• Generally considered safe during pregnancy: Hydroxychloroquine, sulfasalazine (at doses <2g/day)
• Limited data but likely safe: Certolizumab (minimal placental transfer)
• Discontinue before conception: TNF inhibitors (except certolizumab), rituximab, abatacept

Hepatitis B and C

• Screen all patients before starting biological DMARDs or JAK inhibitors
• Hepatitis B reactivation risk: Particularly with rituximab and TNF inhibitors
• Antiviral prophylaxis: Consider for HBsAg-positive patients

Tuberculosis

• Screen all patients before starting biological DMARDs or JAK inhibitors
• Treat latent TB before starting these medications
• Monitor for TB reactivation during treatment

Monitoring Requirements

Regular monitoring is essential to detect adverse effects early:

• Complete blood count: Every 1-3 months for most DMARDs
• Liver function tests: Every 1-3 months for methotrexate, leflunomide, and JAK inhibitors
• Renal function: Every 3-6 months for drugs with renal clearance
• Lipid profile: For JAK inhibitors and tocilizumab (can increase lipid levels)
• Ophthalmologic examination: Annually for hydroxychloroquine

Common Pitfalls to Avoid

1. Failure to screen for latent TB before starting biological DMARDs
2. Inadequate vaccination before initiating immunosuppressive therapy
3. Overlooking drug interactions (e.g., NSAIDs with methotrexate)
4. Continuing DMARDs during serious infections
5. Not adjusting doses for renal or hepatic impairment
6. Inadequate contraception for women of childbearing potential on teratogenic DMARDs

By carefully considering these contraindications and implementing appropriate monitoring, clinicians can optimize the safety and efficacy of DMARD therapy for patients with rheumatoid arthritis and other inflammatory conditions.