DMARDs Explained: Methotrexate, Hydroxychloroquine and Other Treatments
Disease-modifying antirheumatic drugs—usually shortened to DMARDs—are central to the treatment of inflammatory arthritis and many systemic autoimmune rheumatic diseases.
Unlike painkillers or anti-inflammatory medicines, DMARDs are intended to change the course of the underlying disease. By controlling immune-driven inflammation, they can reduce symptoms, prevent joint or organ damage and improve long-term function.
Patients are sometimes understandably concerned when a DMARD is described as a “strong” medicine or an immunosuppressant. These treatments do require appropriate selection and monitoring, but many have been used successfully for decades. For someone with active inflammatory disease, the consequences of undertreatment may be considerably greater than the risks of a carefully monitored DMARD.
This article focuses mainly on conventional synthetic DMARDs, including methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, mycophenolate and azathioprine.
What Does “Disease-Modifying” Mean?
A painkiller may reduce pain without changing the inflammation responsible for it. An NSAID can improve pain and stiffness while it is being taken, but does not usually prevent the progression of rheumatoid arthritis or systemic autoimmune disease.
A DMARD aims to control the disease itself. Depending on the condition, this may mean settling joint inflammation, reducing disease flares, preventing erosive joint damage or protecting internal organs.
Improvement is rarely immediate. Conventional DMARDs commonly take several weeks to begin working and may require several months, dose adjustment or combination treatment to achieve their full benefit.
The objective is usually remission or low disease activity with the least treatment burden and toxicity possible.
Different Types of DMARD
DMARD is an umbrella term covering several groups of treatment.
Conventional synthetic DMARDs are traditional tablets or capsules such as methotrexate, sulfasalazine, hydroxychloroquine and leflunomide. Mycophenolate and azathioprine are also conventional immunosuppressive treatments used particularly in systemic autoimmune disease.
Biologic DMARDs are manufactured proteins that target particular parts of the immune response. Examples include anti-TNF, IL-6 and B-cell treatments.
Targeted synthetic DMARDs are tablets that act on specific intracellular immune pathways. JAK inhibitors are the best-known example.
Which category is appropriate depends on the diagnosis. Conventional DMARDs are often used first in rheumatoid arthritis and peripheral inflammatory arthritis. Systemic diseases such as lupus, vasculitis or inflammatory myositis require treatment according to the organs involved.
Conventional DMARDs such as methotrexate and sulfasalazine do not generally treat inflammation confined to the spine in axial spondyloarthritis. Sulfasalazine may sometimes be considered when there is significant peripheral joint involvement, but biologic or targeted treatment is usually needed when axial disease remains active despite appropriate initial management.
Why Early Treatment Matters
The strongest evidence for a therapeutic “window of opportunity” comes from rheumatoid arthritis. Starting an appropriate DMARD early can increase the likelihood of good disease control and reduce irreversible joint damage.
This is why NICE recommends beginning conventional DMARD treatment promptly in newly diagnosed active rheumatoid arthritis rather than waiting to see whether persistent synovitis progresses.
Early treatment is also important in many systemic autoimmune diseases, although the urgency and treatment choice depend on the organs involved. Kidney, lung, muscle, neurological or blood-vessel inflammation may require a different approach from disease affecting only the joints or skin.
The principle is not to treat every pain aggressively. It is to identify genuine inflammatory disease and control it before avoidable damage occurs.
Methotrexate
Methotrexate is the most frequently used conventional DMARD in inflammatory arthritis and is often described as the anchor treatment for rheumatoid arthritis. It is also used in psoriatic arthritis and selected connective-tissue diseases, vasculitic conditions and other inflammatory disorders.
At the doses used in rheumatology, methotrexate acts as an immune-modulating anti-inflammatory medicine. This is very different from the much higher doses used in some cancer treatments.
Methotrexate Is Taken Once a Week
The most important practical safety point is that methotrexate for rheumatic disease is taken once a week, never once a day.
The prescription should specify a particular day of the week. Taking a weekly dose every day can cause life-threatening toxicity.
Methotrexate may be given as tablets or as an injection under the skin. The injected form can be helpful when tablets cause significant nausea, absorption is uncertain or an adequate tablet dose has not controlled the disease.
Folic acid is normally prescribed to reduce side effects such as nausea, mouth ulcers and abnormal liver tests. The dose and timing vary, so patients should follow their individual prescription.
Methotrexate Side Effects and Safety
Nausea, fatigue, mouth ulcers and mild hair thinning can occur. Adjusting folic acid, changing the dose or switching to injections may improve tolerability.
Methotrexate can affect blood counts and liver function and is cleared through the kidneys, so regular blood tests are required. Alcohol intake, liver disease, kidney impairment, obesity and interacting medicines can alter its risk.
New persistent breathlessness or a dry cough requires prompt assessment because methotrexate can rarely cause inflammatory lung injury. Severe mouth ulceration, unexplained bruising, significant infection or marked gastrointestinal symptoms also require advice.
Trimethoprim and co-trimoxazole can interact dangerously with methotrexate and should generally be avoided unless a specialist who understands the interaction has specifically advised otherwise. Patients should mention methotrexate whenever another clinician or pharmacist is considering a new medicine.
Sulfasalazine
Sulfasalazine is a long-established oral DMARD used in rheumatoid arthritis, psoriatic arthritis and other forms of peripheral inflammatory arthritis. It may be prescribed alone or in combination with methotrexate or hydroxychloroquine.
The dose is commonly increased gradually to improve gastrointestinal tolerability. Nausea, abdominal discomfort, headache and rash may occur. It can harmlessly turn urine and other body fluids orange or yellow.
Regular blood tests are initially required because sulfasalazine can occasionally affect the liver or blood-cell production. Monitoring may become less frequent after a sustained period of stability, according to local guidance and individual risk.
Sulfasalazine can temporarily reduce sperm count or sperm movement in some men. This normally recovers after the treatment is stopped and does not appear to cause permanent infertility.
Hydroxychloroquine
Hydroxychloroquine is used widely in lupus and related connective-tissue diseases. It may also be used for mild rheumatoid or palindromic inflammatory arthritis, often in combination with another DMARD.
It is an immune-modulating medicine rather than a broad immunosuppressant and does not usually require routine blood tests specifically to detect drug toxicity. It may take several months to produce its full benefit.
Hydroxychloroquine is generally well tolerated. Gastrointestinal symptoms, headache and skin reactions can occur. Dosing should take account of body weight and kidney function.
Hydroxychloroquine and Retinal Monitoring
Long-term hydroxychloroquine treatment can damage the retina. The risk relates particularly to dose, treatment duration, kidney impairment, previous chloroquine exposure and concurrent tamoxifen use.
Current UK guidance recommends annual retinal monitoring after the equivalent of five years of continuous treatment. Patients at higher risk should normally begin annual monitoring after one year. High-risk factors include renal impairment, tamoxifen use and a hydroxychloroquine dose above 5 mg/kg of actual body weight per day.
Routine baseline retinal screening is not currently recommended for every new patient in the UK, although ordinary optometric care remains important.
Retinal monitoring can identify toxicity before the patient notices visual symptoms. The prescribing clinician then considers the findings with the ophthalmology team. Patients should not stop hydroxychloroquine themselves solely because of an uncertain test result, because disease control and the strength of the eye findings both need to be considered.
Leflunomide
Leflunomide is an oral DMARD used mainly in rheumatoid arthritis and psoriatic arthritis. It can be an alternative when methotrexate is unsuitable or ineffective.
It is normally taken once daily. Diarrhoea, nausea, hair thinning and skin reactions can occur. Leflunomide can raise blood pressure and affect blood counts or liver function, so blood tests and blood-pressure monitoring are required.
The medicine and its active metabolite can remain in the body for a prolonged period. If rapid removal is necessary because of significant toxicity or pregnancy planning, a specialist may prescribe a cholestyramine washout procedure.
Combining leflunomide with methotrexate can be effective but may increase liver or blood toxicity, so closer monitoring is generally needed.
Mycophenolate Mofetil
Mycophenolate is used mainly for systemic autoimmune disease rather than routine rheumatoid arthritis. It is particularly valuable in conditions such as lupus nephritis, connective-tissue disease-associated interstitial lung disease and selected cases of vasculitis or inflammatory myositis.
It reduces lymphocyte activity and can help protect organs from continuing immune-mediated inflammation. The dose is usually increased according to tolerance and clinical need.
Diarrhoea, abdominal discomfort and nausea are relatively common. Mycophenolate can also reduce blood-cell counts and increase susceptibility to infection, so regular blood monitoring is required.
Different formulations of mycophenolate are not always directly interchangeable. Patients should check unexpected changes in the name, formulation or dose with their prescriber or pharmacist.
Azathioprine
Azathioprine is another established conventional immunosuppressive treatment used in lupus, vasculitis, inflammatory myositis and other connective-tissue diseases. It is sometimes used to maintain disease control after more intensive initial treatment and can be an important option when pregnancy-compatible therapy is required.
Before treatment, thiopurine methyltransferase—usually shortened to TPMT—may be measured because reduced TPMT activity increases the risk of bone-marrow toxicity. A normal result does not remove the need for subsequent blood monitoring.
Azathioprine can cause nausea and may affect blood counts or liver function. Pancreatitis and significant allergic reactions occur less commonly. New severe abdominal pain, fever, unexplained bruising or symptoms of infection should be reported promptly.
What Happens Before a DMARD Is Started?
The pretreatment assessment depends on the proposed medicine and the patient’s health.
It usually includes a full blood count, liver and kidney tests and review of other medication. Screening for relevant infections, vaccination history, pregnancy plans and previous liver, kidney, lung or gastrointestinal problems may also be necessary.
The clinician should be clear about the diagnosis being treated, the expected benefit, when improvement might occur and how success will be measured. Patients should also know who is responsible for prescriptions, blood monitoring and responding to abnormal results.
These arrangements are particularly important when care is shared between a specialist and a GP.
How Often Are Blood Tests Required?
There is no single monitoring schedule appropriate for every DMARD and every patient.
Updated British Society for Rheumatology guidance recommends a risk-stratified approach. Blood tests are generally closer together after treatment begins or the dose changes. A common approach includes a test approximately two weeks after starting and then regular testing through the first three to six months.
Once treatment and results are stable, monitoring can usually become less frequent. For many conventional DMARDs this may mean testing every three to six months, although higher-risk patients, particular drug combinations and people with kidney, liver or other relevant health problems may need closer surveillance.
Hydroxychloroquine is an important exception because it does not ordinarily require routine blood tests specifically for drug toxicity. Its principal long-term monitoring issue is the retina.
The exact schedule provided by the prescribing team should take precedence over a generic timetable.
Infections and DMARD Treatment
Some DMARDs increase susceptibility to infection, but the effect varies considerably between treatments and doses.
Patients should seek advice for a serious infection, persistent fever, significant breathlessness or an infection requiring hospital treatment. Whether a DMARD should be temporarily withheld depends on the medicine, infection and stability of the underlying rheumatic disease.
Patients should not automatically stop treatment for every minor cough or cold. Equally, they should not continue a significantly immunosuppressive medicine through a serious infection without advice.
Hydroxychloroquine is not normally stopped because of an ordinary infection. Management of methotrexate, leflunomide, mycophenolate and azathioprine may differ according to the clinical circumstances.
Vaccination
Vaccination helps reduce preventable infection in people with autoimmune disease. Influenza, COVID-19, pneumococcal and shingles vaccination may be recommended according to age, treatment and individual risk.
Non-live vaccines can generally be given during conventional DMARD treatment, although the immune response may sometimes be reduced. Live vaccines require individual assessment because suitability depends on the medicine and the total degree of immunosuppression.
In selected adults with stable disease, the specialist may advise a short pause in methotrexate after influenza or COVID-19 vaccination to improve the immune response. Patients should not pause treatment unless this has been agreed, because interruption can also increase the risk of a disease flare.
DMARDs, Pregnancy and Fertility
Pregnancy planning should be discussed before conception because the recommendations differ markedly between medicines. Stopping an effective treatment without an alternative can also allow autoimmune disease to flare, which may itself create pregnancy risks.
Hydroxychloroquine is compatible with pregnancy and breastfeeding and is commonly continued in lupus. Sulfasalazine is also compatible, with higher-dose folic acid advised around conception and during the first trimester. Azathioprine can be used during pregnancy and breastfeeding when clinically required.
Methotrexate must not be taken during pregnancy and should be stopped at least one month before planned maternal conception. Leflunomide is not used during pregnancy and normally requires a cholestyramine washout before maternal conception. Mycophenolate must be stopped at least six weeks before planned maternal conception and replaced with an appropriate alternative.
Current BSR guidance considers paternal exposure to low-dose methotrexate, leflunomide and mycophenolate compatible with pregnancy. Sulfasalazine can temporarily reduce male fertility, but this is usually reversible.
Because individual circumstances and recommendations can change, both women and men should discuss family planning with their rheumatology team rather than stopping medication independently.
What If the First DMARD Does Not Work?
An inadequate response to one DMARD does not mean that all disease-modifying treatment will fail.
The dose may need to be optimised, adherence or absorption considered, or another conventional DMARD added. Some people respond better to a different medicine, while others require combination treatment.
If inflammatory disease remains active despite appropriate conventional therapy, a biologic or targeted synthetic DMARD may be considered. The choice depends on the diagnosis, previous treatments, other medical conditions, infection risk and patient preference.
Persistent pain does not always mean that inflammation remains active. Osteoarthritis, tendon disease, previous structural damage, poor sleep or fibromyalgia may contribute to symptoms even when inflammatory disease is controlled. Escalating immunosuppression is unlikely to help unless there is evidence that active inflammation remains the problem.
Are DMARDs Safe for Long-Term Use?
DMARDs can be used safely and effectively for many years when the medicine is appropriate, monitoring is reliable and emerging problems are addressed.
No effective treatment is completely free from risk. The relevant comparison is therefore not DMARD treatment versus no risk; it is the risk of treatment compared with the risk of uncontrolled disease.
Persistent inflammatory arthritis can cause irreversible joint damage and disability. Systemic autoimmune diseases can affect the lungs, kidneys, blood vessels, muscles or other organs. Good disease control may also reduce dependence on repeated or prolonged corticosteroid treatment.
The safest plan is one in which the diagnosis is secure, the treatment has a defined purpose, monitoring responsibilities are clear and the need for medication is reviewed over time.
The Bottom Line
DMARDs treat the underlying immune-mediated inflammation in inflammatory arthritis and systemic autoimmune rheumatic disease.
Methotrexate, sulfasalazine, hydroxychloroquine and leflunomide are used particularly in inflammatory arthritis. Mycophenolate and azathioprine have important roles in lupus, connective-tissue disease, vasculitis and other systemic conditions.
The medicines differ substantially. Methotrexate must be taken once weekly. Hydroxychloroquine requires appropriately timed retinal monitoring but not routine toxicity blood tests. Other conventional DMARDs generally require regular blood monitoring. Infection, vaccination and pregnancy advice must be tailored to the particular treatment.
For most patients, the purpose of a DMARD is not simply to reduce pain. It is to control inflammation, protect long-term health and make sustained remission or low disease activity possible.
Related Reading
Rheumatoid arthritis: symptoms, diagnosis and treatment
Anti-TNF treatments in rheumatology
Trusted Patient Information
Arthritis UK provide overview of disease-modifying anti-rheumatic drugs, how they work, and common side effects.
Please note, these posts are for general information only and do not constitute medical advice. Dr Singh would encourage you to speak to your healthcare professional to be assessed and managed for your specific symptoms.