DMARDs Explained: Methotrexate, Sulfasalazine, Hydroxychloroquine, Mycophenolate and Leflunomide
Disease-modifying anti-rheumatic drugs (DMARDs) are the foundation of treatment for many inflammatory and autoimmune rheumatic diseases. They work by suppressing the immune-driven inflammation that causes pain, swelling, stiffness and long-term joint or organ damage.
Although these medications are often described as “strong” or “immunosuppressive”, they have been used safely and effectively for decades and remain the cornerstone of modern rheumatology care.
What Are DMARDs?
DMARDs are medications that modify the underlying disease process, rather than simply treating symptoms.
Unlike painkillers or anti-inflammatory drugs, they:
suppress immune-mediated inflammation
reduce disease activity
prevent long-term joint and organ damage
improve long-term outcomes and quality of life
They are used in conditions such as:
rheumatoid arthritis
psoriatic arthritis
axial spondyloarthritis
lupus
inflammatory myositis
vasculitis
connective tissue diseases
Why Are DMARDs Started Early?
In most inflammatory rheumatic diseases there is a recognised “window of opportunity”, where early treatment leads to better long-term outcomes.
Starting DMARDs early:
improves symptom control
increases the chance of remission
reduces irreversible joint damage
improves long-term function
This is why modern rheumatology focuses on early diagnosis and prompt treatment, rather than waiting for disease progression.
Methotrexate
Methotrexate is the most commonly prescribed DMARD in rheumatology and is considered the anchor drug for rheumatoid arthritis.
How It Works
At the low doses used in rheumatology, methotrexate acts as an immune modulator rather than a chemotherapy drug. It suppresses key inflammatory pathways involved in autoimmune disease.
What Conditions Is It Used For?
rheumatoid arthritis
psoriatic arthritis
inflammatory arthritis
some connective tissue diseases
vasculitis (in selected cases)
How Is It Taken?
once weekly (never daily)
as tablets or subcutaneous injections
usually combined with folic acid taken on a different day
Why the Dose Is Increased Gradually
Methotrexate is usually started at a low dose and increased gradually over several weeks.
This approach is used to:
improve tolerability
reduce early side effects
allow the body to adjust
find the lowest effective dose
For example:
often started at 7.5–10 mg once weekly
gradually increased (e.g. to 15–25 mg weekly) depending on response and tolerance
Because methotrexate is titrated slowly, early side effects often improve with time, dose adjustment, folic acid supplementation, or switching from tablets to injections.
Sulfasalazine
Sulfasalazine is a long-established DMARD used particularly in inflammatory arthritis.
What Conditions Is It Used For?
rheumatoid arthritis
psoriatic arthritis
peripheral spondyloarthritis
Key Points
taken orally, usually twice daily
slow onset (6–12 weeks)
generally well tolerated
useful in combination therapy
Hydroxychloroquine
Hydroxychloroquine is one of the mildest DMARDs and is widely used in autoimmune diseases.
What Conditions Is It Used For?
rheumatoid arthritis
lupus
connective tissue diseases
inflammatory arthritis
Key Points
mild immune-modulating effect
slow onset (8–16 weeks)
generally very well tolerated
usually started at full therapeutic dose
does not require dose titration
Hydroxychloroquine and the Eyes
Hydroxychloroquine can very rarely affect the retina at the back of the eye when taken long-term.
Important points:
the risk is very low at standard doses
modern screening has made this complication extremely uncommon
baseline and periodic eye checks are recommended
the drug is usually stopped if any early changes are detected
When prescribed at appropriate doses and monitored correctly, hydroxychloroquine is considered a very safe long-term medication.
Leflunomide
Leflunomide is an effective alternative to methotrexate for inflammatory arthritis.
What Conditions Is It Used For?
rheumatoid arthritis
psoriatic arthritis
Key Points
taken once daily
similar effectiveness to methotrexate
slow onset (8–12 weeks)
usually started at a fixed dose
requires regular blood monitoring
Mycophenolate Mofetil
Mycophenolate is a more potent immunosuppressive DMARD used mainly in systemic autoimmune disease.
What Conditions Is It Used For?
lupus (especially kidney or lung involvement)
vasculitis
inflammatory myositis
connective tissue disease-related lung disease
Key Points
not usually used for routine inflammatory arthritis
particularly valuable in organ-threatening disease
requires careful blood monitoring
How Long Do DMARDs Take to Work?
DMARDs are slow-acting medications.
Most take:
6–16 weeks to show benefit
several months for full effect
Because of this, short-term treatments such as corticosteroids are sometimes used as a temporary bridge while DMARDs are taking effect.
Side Effects and Monitoring
All DMARDs can cause side effects, but serious complications are uncommon when they are:
prescribed appropriately
monitored correctly
used at the lowest effective dose
Common Side Effects
Most side effects are mild and manageable, particularly in the early months of treatment.
Common examples include:
nausea or indigestion
fatigue
headache
mouth ulcers (especially with methotrexate)
mild hair thinning
increased susceptibility to minor infections
Many of these improve with:
dose adjustment
folic acid supplementation
switching between tablet and injection formulations
simple supportive treatments
Less Common but More Serious Side Effects
More serious side effects are uncommon, particularly with appropriate monitoring.
These can include:
liver inflammation
low white blood cell counts
lung inflammation (rare with methotrexate)
severe allergic reactions (very rare)
This is why structured blood-test monitoring is a routine and essential part of DMARD therapy.
When abnormalities are detected early, problems can almost always be reversed by:
dose reduction
temporary drug interruption
switching to an alternative DMARD
Blood-Test Monitoring: How Often Is It Done?
Regular blood tests are required to ensure DMARDs remain safe.
Although schedules vary slightly between drugs and individuals, a typical approach is:
every 2–4 weeks for the first 2–3 months
then every 4–8 weeks once stable
sometimes every 12 weeks in long-term stable patients
These blood tests monitor:
liver function
kidney function
blood cell counts
This structured monitoring is evidence-based and designed to detect problems early, before they become clinically significant.
DMARDs, Fertility and Pregnancy
Family planning is an important consideration when choosing DMARD therapy, particularly for women of child-bearing age and men wishing to father a child.
Different DMARDs have very different safety profiles in pregnancy.
Methotrexate
not safe in pregnancy
must be stopped at least 1-3 months before conception
avoided in women planning pregnancy
associated with miscarriage and birth defects
Leflunomide
not safe in pregnancy
can remain in the body for a prolonged period
requires a drug elimination procedure before conception
avoided in both women and men planning pregnancy
Hydroxychloroquine
safe in pregnancy
often continued throughout pregnancy in lupus and inflammatory arthritis
does not impair fertility
considered one of the safest DMARDs
Sulfasalazine
generally safe in pregnancy
often continued
men may experience reversible low sperm counts
folic acid supplementation is recommended
Mycophenolate Mofetil
not safe in pregnancy
strongly associated with birth defects
must be stopped well in advance of conception
requires careful specialist planning
Why Specialist Advice Matters
Because these drugs differ so significantly:
pregnancy plans should always be discussed in advance
treatment can usually be adjusted safely
disease control can often be maintained with pregnancy-compatible drugs
This avoids both disease flares and unnecessary risk to the baby.
Are DMARDs Safe Long-Term?
Yes — when monitored properly, DMARDs are very safe long-term.
They have:
been used for decades
extensive safety data
well-established monitoring protocols
For most patients, the risks of untreated inflammation and active disease far outweigh the risks of DMARD therapy.
What If DMARDs Don’t Work?
If disease remains active despite conventional DMARDs, additional therapies are available.
These include:
biologic drugs (such as anti-TNF agents)
targeted synthetic DMARDs (such as JAK inhibitors)
(Related reading: Anti-TNF Treatments in Rheumatology – What Patients Should Know)
Why Treatment Is Individualised
There is no single “best” DMARD for everyone.
Treatment decisions are based on:
diagnosis
disease severity
organ involvement
other medical conditions
pregnancy plans
patient preference
This personalised approach maximises benefit and minimises risk.
In Summary
DMARDs suppress immune-driven inflammation
They prevent long-term joint and organ damage
Methotrexate is the most commonly used first-line drug
Sulfasalazine and hydroxychloroquine are often used in combination
Leflunomide is an effective alternative
Mycophenolate is used for systemic autoimmune disease
Some DMARDs are started low and increased gradually
All DMARDs require regular blood monitoring
Different DMARDs have different pregnancy safety profiles
Modern rheumatology aims for remission or low disease activity
Trusted Patient Information Resources
Arthritis UK provide overview of disease-modifying anti-rheumatic drugs, how they work, and common side effects.
Methotrexate
Sulfasalazine
Hydroxychloroquine
Leflunomide
Mycophenolate
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.