What are the common side effects of disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, and hydroxychloroquine, and biologic agents like etanercept, adalimumab, and infliximab in a patient with rheumatoid arthritis?

Side Effects of Rheumatoid Arthritis Medications

Disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis carry distinct toxicity profiles that require vigilant monitoring, with methotrexate causing primarily hepatotoxicity and bone marrow suppression, sulfasalazine causing gastrointestinal and hematologic effects, hydroxychloroquine causing retinal toxicity, and biologic agents significantly increasing infection risk including tuberculosis reactivation and opportunistic infections. 1, 2, 3

Conventional Synthetic DMARDs (csDMARDs)

Methotrexate

Methotrexate is the first-line agent but carries significant toxicity requiring close monitoring 4:

Most Common Side Effects:

• Ulcerative stomatitis, leukopenia, nausea, and abdominal distress are the most frequently reported 1
• Malaise, undue fatigue, chills, fever, dizziness, and decreased resistance to infection occur commonly 1

Serious Adverse Effects:

• Hepatotoxicity: Acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, and elevated liver enzymes 1
• Bone marrow suppression: Suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, and agranulocytosis 1
• Pulmonary toxicity: Interstitial pneumonitis with reported deaths, respiratory fibrosis, respiratory failure, and chronic interstitial obstructive pulmonary disease 1
• Renal toxicity: Severe nephropathy or renal failure, azotemia, proteinuria 1
• Opportunistic infections: Pneumocystis carinii pneumonia (most common), cytomegalovirus infection, sepsis (sometimes fatal), nocardiosis, histoplasmosis, cryptococcosis, and disseminated herpes simplex 1
• Neurologic effects: Transient cognitive dysfunction, mood alteration, leukoencephalopathy, encephalopathy, headaches, drowsiness, blurred vision, transient blindness, speech impairment, hemiparesis, and seizures 1

Sulfasalazine

Sulfasalazine is recommended when methotrexate is contraindicated 4:

Most Common Side Effects:

• Anorexia, headache, nausea, vomiting, gastric distress, and reversible oligospermia occur in approximately one-third of patients 2

Less Frequent but Important:

• Skin rash, pruritus, urticaria, fever, Heinz body anemia, hemolytic anemia, and cyanosis (approximately 1 in 30 patients) 2
• Risk increases with daily dosage ≥4 g or serum sulfapyridine levels >50 mcg/mL 2

Serious Adverse Effects:

• Blood dyscrasias: Aplastic anemia, agranulocytosis, leukopenia, megaloblastic anemia, purpura, thrombocytopenia, methemoglobinemia, and myelodysplastic syndrome 2
• Hypersensitivity reactions: Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, DRESS syndrome, anaphylaxis, serum sickness syndrome 2
• Pulmonary: Interstitial lung disease, pneumonitis with or without eosinophilia, fibrosing alveolitis, pleuritis 2
• Cardiac: Pericarditis with or without tamponade, allergic myocarditis 2
• Hepatic: Hepatitis, hepatic necrosis, fulminant hepatitis sometimes requiring liver transplantation 2
• Neurologic: Transverse myelitis, convulsions, meningitis, Guillain-Barre syndrome, peripheral neuropathy 2
• Renal: Toxic nephrosis with oliguria/anuria, nephritis, nephrotic syndrome, hemolytic-uremic syndrome 2

Hydroxychloroquine

Hydroxychloroquine is often used in combination therapy 4, 5, 6:

Key Toxicity:

• Retinal toxicity: Serious visual changes requiring ophthalmologic monitoring (specific frequency not detailed in provided evidence but well-established in clinical practice) 1

Biologic DMARDs (bDMARDs)

Biologic agents including TNF inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab), abatacept, tocilizumab, sarilumab, and rituximab share common serious risks 4, 3:

TNF Inhibitors (Using Infliximab as Representative Example)

Most Common Side Effects:

• Respiratory infections (sinus infections, sore throat), headache, coughing, stomach pain 3

Serious Infections (Black Box Warning):

• Tuberculosis reactivation: Patients must be tested before initiating therapy 3
• Opportunistic infections: Sometimes fatal, including Pneumocystis carinii pneumonia (most common), cytomegalovirus infection, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, and disseminated herpes simplex 3
• Bacterial, viral, and fungal infections that may lead to hospitalization or death 3

Malignancy Risk:

• Increased risk of lymphoma and other malignancies 3

Cardiovascular Events:

• Heart failure (new onset or worsening) 3
• Symptoms include chest discomfort/pain, arm pain, stomach pain, shortness of breath, anxiety, lightheadedness, dizziness, fainting, sweating, nausea, vomiting, palpitations 3

Hepatotoxicity:

• Serious liver problems including jaundice, dark brown urine, right-sided abdominal pain, fever, severe fatigue 3

Hematologic:

• Body may not produce enough blood cells to fight infections or stop bleeding 3
• Symptoms: persistent fever, easy bruising/bleeding, pallor 3

Neurologic:

• Changes in vision, weakness in arms/legs, numbness/tingling, seizures 3
• Stroke: Can occur within 24 hours of infusion (numbness/weakness of face/arm/leg, confusion, speech problems, vision changes, sudden severe headache) 3

Infusion Reactions:

• Can occur during or up to 2 hours after infusion 3
• Symptoms: fever, chills, chest pain, blood pressure changes, shortness of breath, rash, itching 3

Delayed Allergic Reactions:

• Occur 3-12 days after treatment 3
• Symptoms: fever, rash, headache, sore throat, muscle/joint pain, facial/hand swelling, difficulty swallowing 3

Autoimmune Phenomena:

• Lupus-like syndrome: Chest discomfort, shortness of breath, joint pain, rash on cheeks/arms worsening in sun 3
• New or worsening psoriasis: Red scaly patches or pus-filled raised bumps 3

Pediatric Considerations:

• Children with Crohn's disease showed higher rates of anemia, leukopenia, flushing, viral infections, neutropenia, bone fractures, bacterial infections, and allergic respiratory reactions compared to adults 3

Monitoring Requirements

EULAR and ACR Guidelines Mandate:

• Frequent monitoring every 1-3 months during active disease 4
• Assessment at 3 months with target achievement expected by 6 months 4, 7
• Regular laboratory monitoring including complete blood count, liver function tests, renal function 8
• Testing for hepatitis B, hepatitis C, and tuberculosis before initiating biologic agents 8

Critical Safety Considerations

Common Pitfalls to Avoid:

• Failing to screen for latent tuberculosis before starting biologics can result in fatal disseminated TB 3
• Inadequate monitoring of methotrexate can miss early hepatotoxicity or bone marrow suppression 1
• Continuing biologics during active infection significantly increases mortality risk 3
• Ignoring early signs of opportunistic infections (persistent fever, unusual infections) in immunosuppressed patients 3, 1

When to Stop Therapy:

• Development of serious infection requires immediate discontinuation of biologics 3
• Significant hepatotoxicity, bone marrow suppression, or severe hypersensitivity reactions necessitate stopping the offending agent 1, 2
• New neurologic symptoms or lupus-like syndrome may require cessation 3, 2