Disease-modifying Antirheumatic Drugs

Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Common side effects among the disease-modifying antirheumatic drugs include bone marrow suppression and hepatotoxicity. Leflunomide, methotrexate, and tumor necrosis factor (TNF)-ɑ inhibitors are avoided in pregnancy due to their potential teratogenicity. Hydroxychloroquine and sulfasalazine are safe for use during pregnancy.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview of Antirheumatic Drugs

Definition

Antirheumatic drugs are used to treat rheumatoid arthritis by slowing the progression of the disease.

General indications

Antirheumatic drugs are given for rheumatoid arthritis.

Classification

  • Synthetic drugs:
    • Leflunomide
    • Methotrexate 
    • Sulfasalazine
    • Hydroxychloroquine
  • Biologic agents: tumor necrosis factor (TNF)-ɑ inhibitors

Leflunomide

Table: Leflunomide
Mechanism of action
  • Inhibits dihydroorotate dehydrogenase
  • Interrupts de novo synthesis of pyrimidines
  • Inhibits proliferation of immune cells
Physiologic effects
  • Antiinflammatory effect
  • Antiproliferative effect
Metabolism
  • Hepatic conversion to an active metabolite (teriflunomide)
  • Further metabolism into inactive metabolites
Elimination
  • Time to peak: 6–12 hours
  • Half-life: 18–19 days
Specific indications
  • Rheumatoid arthritis
  • Psoriatic arthritis
Specific contraindications
  • Severe hepatic impairment
  • Previous anaphylaxis
Complications/adverse effects
  • Headache
  • Skin rash
  • Diarrhea
  • Bone-marrow suppression with pancytopenia
  • Hepatotoxicity
  • Teratogenicity
  • Give pregnancy test before starting leflunomide to exclude pregnancy, and advise use of effective contraception during leflunomide treatment.
DHF: dihydrofolate
THF: tetrahydrofolate

Methotrexate

Table: Methotrexate
Mechanism of action
  • Folate analog
  • Inhibits DHF reductase:
    • ↓ Conversion of DHF to THF
    • ↓ Pyrimidine and purine synthesis
    • ↓ Proliferation of immune cells
Physiologic effects
  • Immunosuppressant
Metabolism
  • Onset of action: 3–6 weeks
  • Time to peak: 0.75–6 hours
Elimination
  • Half-life:
    • Children: 0.75–5.8 hours
    • Adults: 3–15 hours (IV has a longer half-life than oral)
Specific indications
  • Neoplastic diseases treated with methotrexate:
    • Leukemia (e.g., acute lymphoblastic leukemia)
    • Lymphoma
    • Sarcoma
    • Choriocarcinoma
  • Nonneoplastic diseases treated with methotrexate:
    • Rheumatoid arthritis
    • Medical abortion (along with misoprostol)
    • Ectopic pregnancy
    • Inflammatory bowel disease
    • Vasculitis
Specific contraindications
  • Breastfeeding or pregnancy
  • History of anaphylaxis
  • Alcoholism
  • Chronic liver disease
  • Immunodeficiency
  • Blood dyscrasia (e.g., severe anemia)
Complications/adverse effects
  • Bone marrow suppression with pancytopenia:
    • Reversible with leucovorin (folinic acid) rescue
    • High-dose methotrexate should be followed with leucovorin
  • Hepatotoxicity
  • Stomatitis
  • Pulmonary fibrosis
  • Nephrotoxicity
  • Teratogenicity
Methotrexate structure Disease-modifying anti-rheumatic drugs

The structure of methotrexate: a medication used to treat cancer and, as an immunosuppressive medication, conditions like rheumatoid arthritis

Image by Lecturio. License: CC BY-NC-SA 4.0

Sulfasalazine

Table: Sulfasalazine
Mechanism of action
  • Broken down into sulfapyridine and mesalamine by colonic bacteria
  • 5-ASA (mesalamine) inhibits inflammatory prostaglandin production
  • Suppresses TNF-ɑ and IL-1
Metabolism
  • Converted in the colon to sulfapyridine and 5-ASA for absorption
Elimination
  • Average half-life for elimination: 7.5 hours
  • Average time to peak: 6 hours
Specific indications
  • Juvenile rheumatoid arthritis
  • Rheumatoid arthritis
  • Ulcerative colitis
Specific contraindications
  • Known hypersensitivity
  • Obstruction
  • Porphyria
Complications/adverse effects
  • Anaphylaxis
  • Hepatotoxicity
  • Stomatitis
  • Reversible oligospermia
  • Hepatotoxicity
  • Hemolytic anemia
5-ASA: 5-aminosalicylic acid
TNF: tumor necrosis factor
IL-1: interleukin-1

Hydroxychloroquine

Table: Hydroxychloroquine
Mechanism of action
  • Disrupts digestive vacuoles:
    • Increases pH
    • Interferes with lysosomal degradation of hemoglobin
Physiologic Effects
  • Suppresses TNF-ɑ and IL-1
  • Decreases inflammation
MetabolismAbsorption is incomplete.
Elimination
  • Eliminated by the kidneys, excreted in the urine
  • Half-life for elimination: 40 days
Specific indications
  • Lupus
  • Malaria
  • Rheumatoid arthritis
Specific contraindicationsKnown hypersensitivity
Complications/adverse effects
  • Retinopathy
  • Itching in dark-skinned individuals
  • QT prolongation with the risk of torsades de pointes
TNF: tumor necrosis factor
IL-1: interleukin-1

TNF-ɑ inhibitors

Table: TNF-ɑ inhibitors
Agents
  • Monoclonal antibodies:
    • Adalimumab
    • Golimumab
    • Certolizumab
    • Infliximab
  • Receptor fusion protein: etanercept
Mechanism of action
  • Inactivate TNF-ɑ
  • Decrease inflammation
Specific indications
  • Rheumatoid arthritis
  • Crohn’s disease
  • Certain cancers (e.g., infliximab for renal cell cancer)
NotePerform tuberculin skin test before prescribing TNF-ɑ inhibitors.
Complications/adverse effects
  • Congestive heart failure
  • Demyelination
  • Infection
  • Malignancy (hepatosplenic T-cell lymphoma)
  • Reactivation of tuberculosis
  • Reactivation of HBV infection
  • Drug-induced lupus (etanercept)
TNF: tumor necrosis factor

Comparison of Antirheumatic Medications

The following table compares and contrasts the antirheumatic drugs:

Table: Disease-modifying antirheumatic drugs
DrugMechanism of actionSide effects
Leflunomide
  • Inhibits dihydroorotate dehydrogenase
  • Interrupts de novo synthesis of pyrimidines
  • Bone-marrow suppression with pancytopenia
  • Hepatotoxicity
  • Teratogenicity
Methotrexate
  • Folate analog
  • Inhibits dihydrofolate reductase: decreased THF production
  • Interrupts de novo synthesis of pyrimidines and purines
  • Bone-marrow suppression with pancytopenia
  • Hepatotoxicity
  • Stomatitis
  • Pulmonary fibrosis
  • Nephrotoxicity
  • Teratogenicity
Sulfasalazine
  • 5-ASA (mesalamine) inhibits inflammatory prostaglandin production
  • Suppresses TNF-ɑ and IL-1
  • Sulfa allergy
  • Hepatotoxicity
  • Stomatitis
  • Reversible oligospermia
  • Hemolytic anemia
Hydroxychloroquine
  • Suppresses TNF-ɑ and IL-1
  • Retinopathy
  • Itching in dark-skinned individuals
  • QT prolongation with the risk of torsades de pointes
TNF-ɑ inhibitors
  • Inactivates TNF-ɑ
  • Congestive heart failure
  • Demyelination
  • Infection
  • Malignancy
  • Reactivation of tuberculosis
  • Reactivation of HBV infection
  • Drug-induced lupus (etanercept)
TNF: tumor necrosis factor
5-ASA: 5-aminosalicylic acid
IL-1: interleukin-1
HBV: hepatitis B virus

References

  1. Lexicomp. Hydroxychloroquine: Drug information. UpToDate. Retrieved May 31, 2021, from https://www.uptodate.com/contents/hydroxychloroquine-drug-information
  2. Kirkham, B. (2020). Tumor necrosis factor-alpha inhibitors: An overview of adverse effects. UpToDate. Retrieved May 31, 2021, from https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors-an-overview-of-adverse-effects

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details