Disease-Modifying Antirheumatic Drugs (DMARDs)
Key points
- DMARDs: drugs that suppress the underlying inflammatory disease process and slow or prevent structural joint damage, in contrast to NSAIDs and analgesics, which only treat symptoms.
- Methotrexate: the first-line conventional DMARD across most inflammatory arthritis - a weekly dose with folic acid, monitored with regular FBC, LFTs and U&Es. Confusing weekly with daily dosing is a recognised, potentially fatal prescribing error.
- Safest in pregnancy: hydroxychloroquine and sulfasalazine (with folic acid) can be continued in pregnancy; methotrexate and leflunomide are teratogenic and must be stopped well in advance of conception.
- Before any biologic: screen for latent TB, hepatitis B and C, and ensure vaccinations are up to date, since live vaccines become contraindicated once treatment starts.
- Combination therapy: biologics are usually given alongside methotrexate, which reduces the formation of anti-drug antibodies and improves efficacy.
- JAK inhibitors: carry an increased risk of venous thromboembolism, major cardiovascular events and malignancy, particularly in patients over 65 or with cardiovascular risk factors - used with caution in that group.
- Leflunomide washout: has an extremely long half-life and needs an active washout procedure (cholestyramine) before conception, not simply stopping the drug.
- Treat-to-target: DMARDs are started early and escalated according to disease activity, aiming for remission or low disease activity rather than symptom control alone.
Introduction
Disease-modifying antirheumatic drugs (DMARDs) are the drugs that alter the underlying course of inflammatory joint disease - suppressing the immune and inflammatory processes that drive synovitis - rather than simply relieving symptoms. This is the fundamental distinction from NSAIDs and analgesics: a DMARD can prevent or slow the erosive joint damage that causes long-term disability, which is why they are started as early as possible once an inflammatory arthritis is diagnosed.1
DMARDs are grouped into three classes - conventional synthetic (csDMARDs), biologic (bDMARDs) and targeted synthetic (tsDMARDs) - each already introduced within the individual disease articles in this section. This article draws them together as a single pharmacology reference, since prescribing safety questions cut across every condition that uses them.
Conventional synthetic DMARDs
| Drug | Mechanism | Key toxicities | Monitoring |
|---|---|---|---|
| Methotrexate | Folate antagonist - inhibits dihydrofolate reductase, reducing lymphocyte proliferation | Hepatotoxicity, bone marrow suppression, pneumonitis, mouth ulcers, teratogenic | FBC, U&E, LFT every 1-2 weeks initially, then every 2-3 months once stable |
| Sulfasalazine | Anti-inflammatory and immunomodulatory; mechanism not fully defined | Bone marrow suppression, hepatotoxicity, reversible oligospermia, rash | FBC and LFT regularly, especially in the first few months |
| Hydroxychloroquine | Antimalarial - interferes with antigen presentation and lysosomal function | Retinopathy (dose-dependent), rare cardiomyopathy | Baseline and then annual ophthalmological screening (from year 5) |
| Leflunomide | Inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis in proliferating lymphocytes | Hepatotoxicity, hypertension, peripheral neuropathy, diarrhoea, teratogenic with a very long half-life | FBC, LFT, blood pressure |
Sulfasalazine requires caution in sulfonamide allergy and in G6PD deficiency, where it can precipitate haemolysis. Leflunomide's active metabolite has a half-life measured in weeks, so simply stopping the drug before conception is not enough - an active washout with cholestyramine is needed to clear it from the body.
Biologic DMARDs
Biologics are engineered proteins that target a specific molecule in the inflammatory cascade, in contrast to the broader immunosuppressive action of conventional DMARDs.2
| Class | Examples | Target | Notable safety points |
|---|---|---|---|
| Anti-TNF | Adalimumab, etanercept, infliximab, certolizumab, golimumab | Tumour necrosis factor-alpha | TB reactivation, avoid in significant heart failure (NYHA III/IV), rare lupus-like syndrome or demyelination |
| Anti-CD20 | Rituximab | B lymphocytes | Infusion reactions, hepatitis B reactivation, hypogammaglobulinaemia with prolonged use, rare PML |
| Anti-IL-6 receptor | Tocilizumab, sarilumab | Interleukin-6 signalling | Bowel perforation risk (particularly with diverticular disease), deranged lipids, neutropenia, raised transaminases |
| T-cell co-stimulation blocker | Abatacept | CD80/86-CD28 co-stimulation | Infection risk, generally well tolerated |
| Anti-IL-17 | Secukinumab, ixekizumab | Interleukin-17 | Can worsen inflammatory bowel disease, candidiasis |
| Anti-IL-12/23 and anti-IL-23 | Ustekinumab, guselkumab, risankizumab | Interleukin-12/23 or 23 alone | Generally well tolerated, infection risk |
| Anti-BAFF/BLyS | Belimumab | B-lymphocyte stimulator | Used specifically in SLE |
Targeted synthetic DMARDs
JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are oral drugs that block Janus kinase enzymes involved in cytokine receptor signalling, giving them a broad effect similar in scope to a biologic but delivered as a tablet.
Apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, is a milder option used in psoriatic arthritis for patients who do not need or cannot have biologic therapy; its main side effects are gastrointestinal (diarrhoea, nausea) and weight loss.
Choosing and combining DMARDs
Methotrexate is first-line across most DMARD-treated conditions, both because of its efficacy and because it is usually combined with a biologic when one is needed, reducing the formation of anti-drug antibodies and improving the biologic's efficacy and durability.
Treatment follows a treat-to-target strategy: start early, review disease activity frequently (using tools such as the DAS28 in rheumatoid arthritis), and escalate through the classes above until remission or low disease activity is achieved, rather than accepting ongoing symptoms as the ceiling of what treatment can do.
Screening and monitoring before and during treatment
- Baseline bloods (FBC, U&E, LFT) before starting any DMARD, with regular monitoring thereafter at intervals set by the specific drug
- Latent TB and hepatitis B/C screening before biologics and JAK inhibitors
- Vaccination review, ideally completed before starting treatment, since live vaccines (MMR, yellow fever, oral typhoid, shingles - the live formulation) are contraindicated once significant immunosuppression begins
- Annual ophthalmological screening from year 5 of hydroxychloroquine treatment, for retinopathy
- Skin surveillance with prolonged immunosuppression, given a modestly increased long-term risk of skin malignancy, particularly with thiopurines and some biologics
Drug safety in pregnancy and breastfeeding
| Generally continued | Generally stopped before conception |
|---|---|
| Hydroxychloroquine | Methotrexate (teratogenic) |
| Sulfasalazine (with folic acid) | Leflunomide (teratogenic; needs active washout) |
| Azathioprine | JAK inhibitors (insufficient safety data, animal teratogenicity) |
| Certolizumab (minimal placental transfer) | Most other anti-TNF agents are individualised - often continued into pregnancy but stopped in the third trimester depending on the agent |
Key prescribing safety points
Summary
The DMARD landscape has expanded rapidly from a handful of conventional synthetic drugs to a wide range of biologic and targeted synthetic agents, each targeting a specific step in the inflammatory cascade. The underlying exam logic stays consistent across the individual disease articles in this section: start a conventional synthetic DMARD (usually methotrexate) early, escalate to a biologic or targeted synthetic agent if disease activity remains high, and build in the screening, monitoring and pregnancy planning that keep these genuinely disease-altering drugs safe to use.
References
- British National Formulary. Disease-modifying antirheumatic drugs. Available here
- NICE NG100. Rheumatoid arthritis in adults: management. 2018, updated 2020. Available here
- Smolen JS, Landewe RBM, Bergstra SA et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Annals of the Rheumatic Diseases. 2023. Available here
- MHRA Drug Safety Update. JAK inhibitors: increased risk of major cardiovascular events, malignancy, venous thromboembolism and serious infection. Available here
- British Society for Rheumatology. Biologics and biosimilars prescribing guidance. Available here
This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.