DMARDs: Methotrexate, Sulfasalazine, Leflunomide, Hydroxychloroquine & Biologic Therapy

DMARDs: complete pharmacology of disease-modifying antirheumatic drugs

Disease-modifying antirheumatic drugs (DMARDs) are a heterogeneous group of medicines used to control inflammatory arthritis and prevent structural damage, disability and extra-articular complications. Unlike NSAIDs, which mainly reduce pain and inflammation without stopping the underlying disease, DMARDs can reduce synovitis, slow erosions and induce sustained low disease activity or remission. Their effects are usually delayed over weeks to months, so short-term NSAID or glucocorticoid “bridging” may be used while the DMARD becomes effective.

Learning objectives

• Define DMARDs and distinguish symptomatic anti-inflammatory drugs from disease-modifying treatment.
• Classify conventional synthetic, biological and targeted synthetic DMARDs, including the historic agents shown in the supplied SlideShare deck.
• Explain the mechanisms, adult doses, indications, contraindications, adverse effects, interactions and monitoring of the major agents.
• Apply treat-to-target principles, infection screening, vaccination and reproductive safety to clinical decisions.
• Recognise DMARD-related emergencies such as methotrexate toxicity, severe infection, hepatotoxicity, cytopenia, biologic infusion reactions and JAK-inhibitor thrombosis.

1. Rheumatoid arthritis and the place of DMARDs

RA is a chronic systemic autoimmune inflammatory disease characterised by persistent synovitis, autoantibodies (often rheumatoid factor and anti-cyclic citrullinated peptide), constitutional symptoms and progressive joint destruction. It may involve the lungs, eyes, skin, nerves, blood vessels and cardiovascular system. Treatment therefore aims not only to relieve pain but to suppress the immune process and preserve long-term function.

What DMARDs can and cannot do

Clinical terms

• csDMARD: conventional synthetic DMARD, such as methotrexate, sulfasalazine, hydroxychloroquine or leflunomide.
• bDMARD: biological DMARD, an engineered antibody or receptor-protein medicine such as adalimumab, infliximab, etanercept, abatacept, rituximab or tocilizumab.
• tsDMARD: targeted synthetic DMARD, usually an oral kinase inhibitor such as tofacitinib, baricitinib or upadacitinib.
• Bridge therapy: a limited course of NSAID or glucocorticoid while the slower DMARD begins to work; the bridge should be tapered as soon as possible.
• Treat-to-target: measure disease activity regularly, adjust treatment if the target is not reached and avoid leaving active disease untreated for months.

2. Classification and treatment strategy

General RA treatment sequence

1. Confirm inflammatory arthritis and assess disease activity, prognosis, comorbidity, pregnancy plans and infection risk.
2. Start a csDMARD promptly—usually methotrexate for moderate/high disease activity unless contraindicated. Hydroxychloroquine or sulfasalazine may suit milder disease or particular comorbidities.
3. Use folic acid with methotrexate and a short, carefully planned bridge if required.
4. Review response regularly using symptoms, swollen/tender joint counts, function, ESR/CRP and a validated disease-activity score.
5. If the target is not achieved, optimise the dose, add another csDMARD or move to a biologic/targeted synthetic DMARD in specialist care.
6. Never continue an ineffective high-risk regimen indefinitely without a documented reassessment.

3. Methotrexate

The supplied deck describes methotrexate (MTX) as a folic-acid antagonist with cytotoxic, immunosuppressant and potent antirheumatoid activity. It is often the anchor drug and has a relatively rapid onset compared with many older DMARDs.

Mechanism

• At high oncological doses, inhibits dihydrofolate reductase and thymidylate synthesis.
• At low weekly RA doses, increased extracellular adenosine and anti-inflammatory effects are particularly important; it reduces activated T-cell and inflammatory-cell activity.
• It suppresses synovial inflammation and slows erosive disease but does not provide immediate analgesia.

Indications

• Moderate-to-severe RA and early inflammatory polyarthritis.
• Psoriatic arthritis, juvenile idiopathic arthritis and other specialist inflammatory diseases.
• Other approved uses include psoriasis and malignancy at different doses and schedules; do not transfer oncology regimens to rheumatology.

Dosing

Adverse effects

• Nausea, anorexia, abdominal discomfort, diarrhoea, stomatitis, mouth ulcers, fatigue and headache.
• Bone-marrow suppression: leukopenia, thrombocytopenia, anaemia or pancytopenia.
• Hepatotoxicity, fibrosis and cirrhosis, particularly with alcohol excess, obesity, diabetes, viral hepatitis or other hepatotoxic drugs.
• Pneumonitis or interstitial lung disease: new dry cough, fever or dyspnoea requires urgent assessment and usually withholding MTX.
• Photosensitivity, alopecia, rash and increased susceptibility to infection.
• Teratogenicity and embryofetal toxicity; avoid in pregnancy and follow specialist contraception guidance.

Contraindications and precautions

• Pregnancy and conception plans without specialist advice; breastfeeding restrictions depend on dose and indication.
• Severe hepatic disease, significant renal impairment, pre-existing blood dyscrasia, active serious infection or severe immunodeficiency.
• Untreated tuberculosis, hepatitis B/C or HIV require a documented specialist plan.
• Use cautiously with pulmonary disease, alcohol use, diabetes, obesity, peptic ulcer disease and concurrent hepatotoxic or nephrotoxic drugs.

Important interactions

• Trimethoprim or co-trimoxazole can produce additive antifolate marrow toxicity and should generally be avoided.
• NSAIDs, penicillins, sulfonamides, tetracyclines and proton-pump inhibitors may reduce renal clearance or increase toxicity in susceptible patients.
• Alcohol and other hepatotoxic medicines increase liver injury risk.
• Live vaccines may be inappropriate during significant immunosuppression; plan vaccination before therapy where possible.

Monitoring

• Before treatment: history and examination, pregnancy status when relevant, CBC/FBC, platelets, creatinine/eGFR, ALT/AST and albumin; screen for hepatitis/TB and obtain chest assessment when indicated.
• After starting or changing dose: repeat CBC, renal function and liver tests frequently according to the local protocol, commonly every 2–4 weeks initially, then every 8–12 weeks once stable.
• Ask at every review about mouth ulcers, bruising, fever, infection, breathlessness, dry cough, nausea, alcohol, adherence and accidental daily dosing.
• Withhold and investigate marked cytopenia, significant liver-test elevation, severe infection or suspected pneumonitis.

4. Sulfasalazine

Sulfasalazine is a common conventional DMARD for RA and also treats inflammatory bowel disease. It is split in the colon into sulfapyridine and 5-aminosalicylic-acid-related metabolites. The deck proposes that it may scavenge toxic oxygen metabolites produced by neutrophils; its full immunomodulatory mechanism is more complex and not completely defined.

Indications and benefits

• RA, especially mild-to-moderate disease or when methotrexate is unsuitable.
• Psoriatic arthritis and peripheral inflammatory arthritis in selected patients.
• Ulcerative colitis and other inflammatory bowel conditions under gastroenterology guidance.

Adult RA dosing

The supplied deck gives a simpler schedule of 500 mg daily for 7 days, then increasing by 500 mg weekly to a maximum of 3 g/day in two or three divided doses. Start low to reduce gastrointestinal intolerance and swallow delayed-release tablets whole.

Adverse effects, contraindications and interactions

• Common: nausea, abdominal pain, diarrhoea, anorexia, headache, malaise, dizziness and orange-yellow discoloration of urine or tears.
• Serious: leukopenia, agranulocytosis, thrombocytopenia, haemolysis (especially in G6PD deficiency), hepatitis, severe skin reactions, pancreatitis and hypersensitivity.
• It may temporarily reduce sperm count and impair fertility; this is usually reversible after stopping.
• Avoid in severe sulfonamide/salicylate hypersensitivity, intestinal or urinary obstruction and porphyria; use specialist advice in severe renal/hepatic disease.
• Interactions include warfarin, digoxin, folate antagonists, methotrexate and drugs that increase marrow or liver toxicity.

Monitoring

Obtain FBC, renal function and liver tests at baseline and repeatedly during dose escalation and maintenance. Ask about rash, fever, sore throat, bruising, jaundice and severe diarrhoea. Stop and urgently investigate suspected agranulocytosis, severe hypersensitivity or hepatitis.

5. Leflunomide

Leflunomide is an oral pyrimidine-synthesis inhibitor. Its active metabolite inhibits dihydro-orotate dehydrogenase, limiting de novo pyrimidine production in activated T lymphocytes. The supplied deck correctly highlights relatively selective inhibition of activated T cells, good oral absorption, a long half-life, diarrhoea, alopecia, raised liver enzymes and risk of hepatic failure.

Indications

• Active RA when methotrexate is unsuitable, ineffective or used in combination under specialist supervision.
• Psoriatic arthritis in some formularies.

Dosing

Adverse effects and cautions

• Diarrhoea, nausea, abdominal pain, weight loss, headache, hypertension, alopecia and rash.
• Hepatotoxicity can be severe or fatal, especially with MTX, alcohol or other hepatotoxic drugs.
• Leukopenia, thrombocytopenia, pancytopenia, peripheral neuropathy, interstitial lung disease and serious infection may occur.
• Contraindicated in pregnancy because of embryofetal toxicity; women and men must follow specialist contraception and conception advice.
• Use caution in renal impairment, liver disease, uncontrolled hypertension, pre-existing neuropathy, immunodeficiency and bone-marrow disorders.

Monitoring and accelerated elimination

Check CBC, ALT/AST, albumin, creatinine and blood pressure at baseline and regularly. A common label-based approach is ALT at least monthly for the first six months and every 6–8 weeks thereafter, with more frequent CBC and liver testing during initiation or combination therapy. If significant hepatotoxicity, severe skin reaction, marrow suppression, serious infection or pregnancy occurs, stop leflunomide and consider an accelerated elimination procedure with cholestyramine or activated charcoal under specialist guidance because the metabolite persists for a long time.

6. Hydroxychloroquine and chloroquine

6.1 Hydroxychloroquine

Hydroxychloroquine (HCQ) is an antimalarial with immunomodulatory activity. It accumulates in lysosomes and alters antigen processing, toll-like receptor signalling and inflammatory-cell activation. Proposed mechanisms in the supplied deck include suppression of T-lymphocyte responses, reduced leukocyte chemotaxis, lysosomal-enzyme stabilisation, inhibition of DNA/RNA synthesis and free-radical trapping.

Indications

• Mild RA or low disease activity, often when a safer, slower conventional DMARD is desired.
• Systemic lupus erythematosus and cutaneous lupus; other specialist autoimmune indications.
• It is slower and usually less potent for erosive high-activity RA than methotrexate.

Adult RA dose

• Initial: 400–600 mg/day once daily or in two divided doses.
• Chronic maintenance: 200–400 mg/day.
• Keep the dose at or below 5 mg/kg/day of actual body weight to reduce retinopathy risk; the manufacturer’s salt and local formulary must be checked.
• Maximum therapeutic effect may require weeks to months. Do not declare failure after only a few days.

Adverse effects and monitoring

• Nausea, diarrhoea, abdominal discomfort, headache, rash, skin pigmentation and bleaching or changes in hair.
• Retinopathy: irreversible macular damage is related to cumulative exposure, duration, renal impairment, tamoxifen and excessive daily dose.
• Neuromyopathy, hypoglycaemia, cardiomyopathy and QT prolongation/ventricular arrhythmia are uncommon but serious.
• Arrange a baseline eye examination within the first year and ongoing retinal screening according to ophthalmology guidance, earlier when risk factors exist. Ask about blurred vision, reading difficulty, colour change or visual field loss.
• Review QT-prolonging medicines and cardiac disease; reduce or stop in suspected cardiomyopathy or retinal toxicity.

6.2 Chloroquine

The deck describes chloroquine as an older antirheumatic option, often reserved for cases where other treatments failed, with effects appearing after a month or more and response in only about half of patients. Because retinal, neuromuscular, cardiac and toxic effects are more concerning, hydroxychloroquine is generally preferred where available.

• Use only specialist-directed, locally licensed dosing; common adult antirheumatic schedules are approximately 250 mg base equivalent daily, but salt strengths differ.
• Baseline and ongoing eye examinations, weight-based dosing, renal adjustment and cardiac-risk review are essential.
• Do not confuse antimalarial treatment doses with chronic rheumatology doses.

7. Historic DMARDs: penicillamine and gold compounds

The supplied 16-slide deck includes these older agents. They are now rarely used because safer, more effective DMARDs and biologics are available, but they remain important for pharmacology examinations and understanding the evolution of RA treatment.

7.1 Penicillamine

Penicillamine is the D-isomer of dimethylcysteine, produced by hydrolysis of penicillin. The deck states that approximately 75% of RA patients responded historically. Its proposed actions include reducing immune responses and IL-1 generation and altering collagen synthesis; the precise antirheumatic mechanism remains uncertain.

• Pharmacokinetics: oral administration, about half the dose absorbed, peak plasma concentration in 1–2 hours, renal excretion.
• Dose: start low, commonly 125–250 mg once daily, then increase by 125–250 mg every 4–8 weeks according to response; specialist maximum is often 500–750 mg/day and rarely up to 1 g/day.
• Administration: usually on an empty stomach and separated from iron, antacids and other minerals because of chelation.
• Adverse effects: rash, stomatitis, anorexia, fever, nausea, vomiting and taste disturbance due to zinc chelation. These may improve after dose reduction.
• Serious toxicity: proteinuria/nephrotic syndrome, haematuria, marrow suppression, autoimmune syndromes, myasthenia-like weakness and pulmonary complications.
• Monitoring: urinalysis/protein, urine protein quantification when indicated, CBC, renal function, liver tests and examination for oral ulcers or rash.

7.2 Gold compounds

Gold is administered as organic complexes. The deck identifies sodium aurothiomalate (deep intramuscular) and auranofin (oral) as the common preparations. Benefits develop slowly over 3–4 months; pain and swelling may reduce and progression of bone/joint damage may diminish. The mechanism is incompletely defined; auranofin can inhibit induction of IL-1 and TNF-alpha.

• Sodium aurothiomalate: historical specialist schedules use a small test dose followed by weekly IM doses, often building toward 25–50 mg weekly; exact preparation and cumulative dose must be confirmed locally.
• Auranofin: common historical adult dose 3 mg twice daily with food; onset is slow and GI/skin toxicity still occurs.
• Adverse effects: rash, pruritus, stomatitis, mouth ulcers, proteinuria, haematuria, thrombocytopenia, leukopenia, aplastic blood dyscrasia, hepatitis, encephalopathy and peripheral neuropathy.
• Monitoring: FBC, urinalysis/protein, renal and liver tests before treatment and at regular intervals; stop early when rash, mouth ulcers, falling counts or proteinuria develop because serious toxicity is less likely when recognised promptly.

8. Immunosuppressant DMARDs mentioned in the reference deck

The supplied slides group immunosuppressants according to the pathway they inhibit:

• Inhibit IL-2 production or action: ciclosporin and tacrolimus.
• Inhibit cytokine gene expression: corticosteroids.
• Inhibit purine or pyrimidine synthesis: azathioprine and related antimetabolites.

Ciclosporin

• Mechanism: calcineurin inhibition reduces IL-2 transcription and T-cell activation.
• Specialist dose: commonly 2.5–5 mg/kg/day orally in two divided doses, adjusted to response, renal function and levels where indicated.
• Uses: selected severe inflammatory or extra-articular disease; not routine first-line RA because toxicity limits use.
• Major toxicity: nephrotoxicity, hypertension, tremor, hypertrichosis, gingival hyperplasia, dyslipidaemia, hyperkalaemia and serious infection.
• Interactions: macrolides, azole antifungals, grapefruit, calcium-channel blockers, NSAIDs, aminoglycosides and other nephrotoxic drugs can increase risk; rifampicin and some anticonvulsants reduce concentrations.
• Monitoring: blood pressure, creatinine/eGFR, electrolytes, liver tests, lipids and drug level when clinically required.

Tacrolimus

• Mechanism: calcineurin inhibition, more potent per milligram than ciclosporin.
• Dose: specialist protocols commonly begin around 0.05–0.1 mg/kg/day divided twice daily, then adjust to trough levels and toxicity; this is not a routine RA prescription.
• Adverse effects: nephrotoxicity, hypertension, tremor, neurotoxicity, hyperglycaemia, hyperkalaemia and infection.
• Use only under specialist monitoring because of narrow therapeutic index and extensive CYP3A4 interactions.

Azathioprine

• Mechanism: prodrug of 6-mercaptopurine; inhibits purine synthesis and lymphocyte proliferation.
• Specialist dose: often 1–2.5 mg/kg/day orally, titrated to response and blood counts.
• Risks: nausea, hepatotoxicity, leukopenia, pancytopenia, pancreatitis, infection and increased long-term malignancy risk.
• Interactions: allopurinol or febuxostat can markedly increase toxicity; if unavoidable, specialist dose reduction is essential. ACE inhibitors, co-trimoxazole and other marrow suppressants also increase risk.
• Check TPMT/NUDT15 activity where available, baseline CBC/LFTs and frequent CBC/LFT monitoring.

9. Biological DMARDs and cytokine modulators

The deck identifies adalimumab, etanercept and infliximab as cytokine modulators used when methotrexate or other DMARDs are inadequate. These medicines should be initiated and monitored by a clinician experienced in rheumatology or immunosuppression.

9.1 TNF inhibitors

TNF-inhibitor class precautions

• Screen for active or latent TB, hepatitis B/C, HIV risk and serious recurrent infection before starting.
• Update non-live vaccines before treatment when possible. Avoid live vaccines during significant biologic immunosuppression.
• Do not start during active serious infection; withhold during hospitalised infection or sepsis until specialist review.
• Urgently assess fever, persistent cough, weight loss, night sweats, unusual skin lesions, diarrhoea, focal infection or new neurological symptoms.
• Avoid combining two biological agents or a biologic with a JAK inhibitor unless a specialist protocol explicitly directs it.

9.2 Abatacept

Abatacept is a selective T-cell co-stimulation modulator: CTLA-4-Ig binds CD80/CD86 and prevents the CD28 co-stimulatory signal needed for full T-cell activation.

• Subcutaneous: 125 mg once weekly, with an optional IV loading dose depending on the product and protocol.
• Intravenous: at weeks 0, 2 and 4, then every 4 weeks; 500 mg if body weight is under 60 kg, 750 mg for 60–100 kg and 1,000 mg over 100 kg.
• Adverse effects: upper-respiratory infection, headache, nausea, infusion/injection reactions and serious infection.
• Use caution in COPD because respiratory adverse effects may be increased; screen and vaccinate as for other biologics.

9.3 Rituximab

Rituximab is an anti-CD20 monoclonal antibody that depletes B cells. It is used for severe RA after inadequate response to TNF inhibitors or in selected situations such as a history of demyelinating disease or certain malignancy risks.

• Dose: 1,000 mg IV on day 1 and day 15, with courses repeated according to response, often around 24 weeks or longer; specialist protocols vary.
• Premedication usually includes an IV corticosteroid such as methylprednisolone 100 mg about 30 minutes before each infusion, plus local antipyretic/antihistamine practice.
• Risks: infusion reaction, bronchospasm, hypotension, severe infection, HBV reactivation, late-onset neutropenia and rare progressive multifocal leukoencephalopathy.
• Check hepatitis B surface antigen and core antibody, immunoglobulins and vaccination status. Avoid live vaccines; response to vaccines may be reduced for months.

9.4 Tocilizumab

Tocilizumab blocks the interleukin-6 receptor. It can be used alone or with conventional DMARDs after inadequate response to prior therapy.

• IV RA regimen: commonly 4 mg/kg every 4 weeks initially, increasing to 8 mg/kg every 4 weeks according to response and product limits.
• Subcutaneous examples: 162 mg every other week, or weekly in selected patients according to weight and response.
• Adverse effects: serious infection, neutropenia, thrombocytopenia, raised liver enzymes, lipid elevation, gastrointestinal perforation (especially with diverticulitis/NSAIDs/steroids) and injection reactions.
• CRP and fever responses may be blunted; do not dismiss infection because inflammatory markers look deceptively normal.
• Monitor CBC, liver enzymes and lipids; avoid initiation with significant cytopenia or transaminase elevation according to the product label.

10. Targeted synthetic DMARDs: JAK inhibitors

JAK inhibitors interrupt intracellular cytokine signalling rather than neutralising one extracellular cytokine. They are oral and effective, but safety warnings require careful selection, especially in older adults, smokers and people with cardiovascular, thrombotic or malignancy risk.

• Screen for TB, hepatitis and infection risk; check CBC, renal/hepatic function and lipids.
• Do not combine with another JAK inhibitor or a biological DMARD; combination with potent immunosuppressants is generally avoided.
• Hold during serious infection, surgery when advised and significant cytopenia.
• Urgently investigate unilateral leg swelling, sudden dyspnoea, chest pain, neurological deficit or acute coronary symptoms for thrombosis or cardiovascular events.
• Use effective contraception and specialist preconception counselling; JAK inhibitors are generally avoided in pregnancy and breastfeeding unless a specialist decision is made.

11. Baseline screening, vaccination and ongoing monitoring

Before any major DMARD

• Confirm diagnosis, disease activity, comorbidities, pregnancy or conception plans and medicine adherence.
• Record CBC/FBC with differential, platelets, creatinine/eGFR, ALT/AST, albumin and blood pressure; add urinalysis and glucose/lipids as appropriate.
• Screen for TB risk and test according to local policy; screen hepatitis B and C before biologic, JAK or substantial immunosuppression.
• Assess vaccination history: influenza, pneumococcal, COVID-19, hepatitis B, HPV and other locally recommended vaccines. Give live vaccines before therapy where possible.
• Document respiratory history, smoking, alcohol, prior malignancy, recurrent infection, heart failure, demyelinating disease, diverticulitis and eye history.

Drug-specific monitoring overview

12. Interactions and high-risk combinations

• MTX + trimethoprim/co-trimoxazole: potentially fatal marrow suppression and mucositis.
• MTX + leflunomide: increased hepatotoxicity and marrow toxicity; specialist monitoring is required.
• Azathioprine + allopurinol/febuxostat: profound myelosuppression unless a specialist makes a major dose reduction and monitors closely.
• DMARD + live vaccine: infection risk; plan timing with the immunisation team.
• Biologic + another biologic/JAK inhibitor: generally avoid because serious infection risk rises without routine additive benefit.
• Ciclosporin/tacrolimus + nephrotoxic drugs or NSAIDs: acute kidney injury and hypertension risk.
• Hydroxychloroquine + QT-prolonging drugs: increased arrhythmia risk, particularly with electrolyte abnormalities or structural heart disease.
• Tocilizumab + CYP-metabolised medicines: falling inflammation can restore CYP activity and alter concentrations of some drugs; review narrow-therapeutic-index medicines.

13. Emergency medicine applications

13.1 DMARD patient with fever or sepsis

Do not attribute fever to “the arthritis” without assessment. Perform ABCDE, cultures and sepsis evaluation, give prompt antimicrobials when indicated and discuss withholding the DMARD. Severe infections may be atypical because immunosuppression blunts fever, CRP or leukocytosis. Look for opportunistic, fungal, TB and hepatitis reactivation when the presentation is unusual.

13.2 Methotrexate overdose

Suspect acute toxicity when a patient takes MTX daily instead of weekly or combines it with a folate antagonist. Features include painful mouth ulcers, severe sore throat, fever, bruising, diarrhoea, pancytopenia, renal failure and sepsis. Stop MTX, obtain urgent FBC, renal/liver tests and specialist/toxicology advice, treat infection and bleeding, and administer folinic acid rescue when directed. Severe cases may require granulocyte-colony stimulating factor, transfusion, renal support or intensive care.

13.3 Biologic infusion reaction

During infliximab, rituximab, abatacept or tocilizumab infusion, stop or slow the infusion for flushing, urticaria, wheeze, hypotension, chest tightness or rigors. For anaphylaxis, follow the emergency protocol with IM adrenaline, airway support, oxygen, fluids and adjuncts. Document the reaction and do not re-challenge without specialist review.

13.4 Leflunomide hepatotoxicity

Jaundice, dark urine, severe nausea, right-upper-quadrant pain or markedly raised transaminases require immediate interruption and liver assessment. Review alcohol, viral hepatitis, paracetamol, MTX and other hepatotoxic medicines. Because the active metabolite persists, specialist-guided cholestyramine or activated-charcoal washout may be required.

13.5 JAK-inhibitor thrombosis

Sudden dyspnoea, pleuritic chest pain, haemoptysis, unilateral leg swelling, focal neurological deficit or acute coronary symptoms require immediate evaluation for pulmonary embolism, DVT, stroke or myocardial infarction. Stop the JAK inhibitor pending specialist assessment and treat according to the emergency diagnosis.

14. Clinical cases

15. High-yield examination summary

• DMARDs change disease progression; NSAIDs and short steroid courses mainly control symptoms and act as bridge therapy.
• Methotrexate is commonly preferred for moderate/high-activity RA. The dose is once weekly, usually titrated from 7.5 mg to 15–25 mg weekly, with folic acid.
• Methotrexate toxicity: mucositis, pancytopenia, hepatotoxicity and pneumonitis. Trimethoprim/co-trimoxazole can be dangerous.
• Sulfasalazine is started low and increased weekly, commonly to 2 g/day and sometimes 3 g/day. Watch for GI effects, rash, cytopenia, hepatitis and haemolysis.
• Leflunomide inhibits pyrimidine synthesis in activated T cells; maintenance is 20 mg daily, with optional 100 mg daily for 3 days loading. Diarrhoea, alopecia and hepatotoxicity are characteristic.
• Hydroxychloroquine is useful in milder disease but has cumulative retinal and rare cardiac toxicity. Keep dose ≤5 mg/kg/day actual weight and screen eyes.
• Penicillamine, gold and chloroquine are historically important but now infrequently used because safer options exist.
• TNF inhibitors include adalimumab, etanercept and infliximab; screen for TB and hepatitis and avoid treatment during serious infection.
• Abatacept blocks T-cell co-stimulation, rituximab depletes CD20 B cells and tocilizumab blocks IL-6 signalling.
• JAK inhibitors are oral but carry serious infection, thrombosis, cardiovascular and malignancy warnings; assess risk before prescribing.
• Every DMARD plan requires baseline tests, vaccination review, patient education, a monitoring schedule and a treat-to-target reassessment.

Sources for further study

• Supplied reference: DMARDs SlideShare deck
• NICE: Rheumatoid arthritis in adults—management recommendations
• American College of Rheumatology guideline for treatment of rheumatoid arthritis
• DailyMed: Methotrexate tablets
• DailyMed: Leflunomide
• DailyMed: Sulfasalazine delayed-release tablets
• DailyMed: Hydroxychloroquine sulfate
• DailyMed: Adalimumab (Humira)
• DailyMed: Etanercept (Enbrel)
• DailyMed: Infliximab
• DailyMed: Abatacept
• DailyMed: Tocilizumab
• DailyMed: Tofacitinib
• DailyMed: Baricitinib
• DailyMed: Upadacitinib