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Disease-Modifying Antirheumatic Drugs (DMARDs)

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Overview

Disease-modifying anti-rheumatic drugs (DMARDs) are a group of drugs that are immunomodulatory (modify the immune response) or immunosuppressive and work to influence the course of a disease.

They are initiated in secondary care and GPs are generally asked to continue prescribing and monitoring.

People taking DMARDs require regular monitoring due to the risk of adverse effects such as:

  • Myelosuppression
  • Gastrointestinal toxicity
  • Renal toxicity
  • Hepatic toxicity
  • Increased risk of infection

Classification

  • Conventional DMARDs – broad immunosuppressive effects:
    • Examples are methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine
  • Biologic DMARDs – genetically engineered proteins that target specific components of the immune system:
    • Tumour necrosis factor (TNF) inhibitors:
      • Examples are adalimumab, infliximab, etanercept, certolizumab, golimumab
    • B-cell inhibitors:
      • Rituximab, belimumab
    • Interleukin inhibitors:
      • Secukinumab, ixekizumab
    • T-cell inhibitors:
      • Abatacept
  • Targeted synthetic DMARDs – target specific immune system components:
    • Tofacitinib – Janus kinase (JAK) inhibitor
    • Baricitinib – JAK1 and JAK2 inhibitor
    • Apremilast – phosphodiesterase type-4 inhibitor

General Management

Patient advice

Patients should seek immediate help if there are signs of:

  • Blood disorders whose features may include:
    • Fever
    • Mouth ulcers
  • Liver toxicity whose features may include:
    • Nausea, vomiting, or abdominal discomfort
    • Dark urine
  • Respiratory effects such as:

Consider stopping the medication and urgently consult a specialist if a person taking DMARDs develops these symptoms.

Methotrexate

Mode of action

Methotrexate is an antifolate drug. It inhibits the enzyme dihydrofolate reductase which is needed for the synthesis of purines and pyrimidines.

Typical dosing

Methotrexate is given once weekly.

Folic acid is routinely co-prescribed with methotrexate to reduce adverse effects and toxicity and is taken on a different day than the methotrexate dose.

Contraindications

  • Active pregnancy or trying for pregnancy – methotrexate is teratogenic
  • Active infections

Interactions

  • NSAIDs:
    • NSAIDs and methotrexate can increase the risk of nephrotoxicity
  • High-dose aspirin:
    • Increased risk of toxicity via possibly altering methotrexate’s pharmacokinetics
  • Any antifolate drugs (trimethoprim/sulfamethoxazole/co-trimoxazole):
    • These are anti-folate drugs as well and can cause acute megaloblastic pancytopenia

Adverse effects

  • Anorexia
  • Nausea
  • Vomiting
  • Diarrhoea
  • Mouth ulcers
  • Gastrointestinal upset
  • Pneumonitis
  • Pulmonary fibrosis
  • Liver damage such as hepatitis, cirrhosis, or fibrosis

Monitoring

Pre-treatment screening:

  • Pregnancy must be excluded before treatment
  • Patients should have FBC, U&Es, and LFTs done before treatment

Monitoring:

  • FBC, U&Es, LFTs every 1-2 weeks until therapy stabilised
  • Then FBC, U&Es, and LFTs every 2-3 months

Conception and contraception

Both men and women should use effective contraception for 6 months without using methotrexate before attempting pregnancy

Pregnancy and breastfeeding

Methotrexate is teratogenic in pregnancy

Do not breastfeed if taking methotrexate, it is present in breastmilk

Sulfasalazine

Mode of action

The mechanism of sulfasalazine is not entirely understood. It metabolises into 5-aminosalicylic acid (5-ASA) which appears to play a bigger role in its therapeutic effect.

Contraindications

  • Salicylate hypersensitivity

Interactions

  • Concomitant use with azathioprine may cause bone marrow suppression
    • This is due to sulfasalazine inhibiting thiopurine methyltransferase

Adverse effects

  • Nausea
  • Oral ulcers
  • Myelosuppression
  • Oligospermia
  • Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Shortness of breath
  • Cough
  • Interstitial lung disease

Monitoring

  • FBC including white cell differential and platelet count, U&Es, and LFTs must be done initially and monthly during the first 3 months
  • After 12 months, monitoring may be stopped

Cautions

  • G6PD deficiency
    • Sulfasalazine may cause haemolysis
  • Acute porphyria
  • History of allergy
  • History of asthma

Leflunomide

Mode of action

The mechanism of leflunomide is not fully understood but is thought to lead to the inhibition of proliferating activated autoimmune lymphocytes.

Contraindications

  • Hypersensitivity
  • Serious infection
  • Severe immunodeficiency

Adverse effects

Monitoring

  • Patients should have an FBC including white cell differential and platelet count, LFTs, and U&Es monitored before treatment then every 2 weeks for 6 months then every 8 weeks
  • Monitor blood pressure

Conception and contraception

  • Effective contraception is essential for at least 2 years without taking leflunomide and at least 3 months in men, with plasma monitoring being required as leflunomide is teratogenic

Pregnancy and breastfeeding

  • Leflunomide is contraindicated as it is teratogenic.
  • Avoid as it is present in milk.

Cautions

  • Leflunomide takes a long time to eliminate from the body. This is important to be mindful of in treatment cessation.
  • Avoid if anaemia present due to causes other than rheumatoid/psoriatic arthritis

Hydroxychloroquine

Mode of action

The mechanism of action of hydroxychloroquine is not entirely understood.

Contraindications

  • Known hypersensitivity
  • Known eye problems

Interactions

  • Hydroxychloroquine prolongs the QT interval, avoid using it with any drugs that prolong the QT interval e.g. amiodarone, clarithromycin, citalopram etc.

Adverse effects

  • Photosensitive skin rashes
  • Nausea
  • Dyspepsia
  • Diarrhoea
  • Headaches
  • Hair loss
  • Tinnitus
  • Visual problems – retinopathy

Monitoring

Pregnancy and breastfeeding

  • May be used in pregnancy if needed
  • May be used if breastfeeding, small amounts may be present in milk

Biologic DMARDs

Adverse effects

  • The main adverse effect is that anti-TNF medication can reactivate latent tuberculosis as TNF-α is needed to maintain the latent state.

Monitoring

  • FBC, U&Es, and LFTs at 3-4 months, then every 6 months
  • Lipids 4-8 weeks after starting treatment

If indicated: assessment for hepatitis B, hepatitis C, tuberculosis, or HIV

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