Conventional Synthetic DMARDs/DMARDs

Conventional Synthetic DMARDs/DMARDs (Methotrexate, Leflunomide, Hydroxychloroquine, Sulphasalazine)

DMARDs (pronounced ‘dee-mard’s) are the most widely used and studied drugs used as therapy for autoimmune arthritis. DMARD stands for disease-modifying antirheumatic drug.

What Is a DMARD?

A DMARD is a medication that slows down the progression of your disease. Other than glucocorticoids (steroids),  conventional synthetic DMARDs have been on the market the longest and have the most evidence to support their use.

DMARDs can be divided into different classifications; conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDs) and biologic DMARDs (bDMARDs).

The most commonly used DMARDs for autoimmune arthritis are those from the csDMARD family, especially methotrexate. This category is often simply referred to as “DMARDs” although it is really a sub-classification of the whole DMARD class of medications.

Leflunomide, hydroxychloroquine and sulphasalazine are often used for mild forms of autoimmune arthritis and other conditions. Other csDMARDs occasionally used for autoimmune arthritis include gold injections, azathioprine and cyclophosphamide.

All DMARDs suppress the immune system, so they can make you more prone to contracting and fighting off infections.

Combination Therapy

Everyone is different. In some cases, one csDMARD might not work by itself or at all. In those cases, a doctor will discuss the following with you:

  • Double therapy: Double therapy is the use of two different medications, usually methotrexate and another csDMARD, such as leflunomide, sulphasalazine or hydroxychloroquine.
  • Triple therapy: Triple therapy uses three medications instead of two. Monitoring for both triple and double therapy is similar to monitoring for csDMARD monotherapy. Initially, closer monitoring may be warranted depending on the combination of medications.

Sometimes, combination therapy will include the use of a biologic or tsDMARD.

Evidence shows that more aggressive treatments are associated with better control of the disease, slower radiological progression (meaning that your X-rays or imaging scans show that your joint damage is slowing down) and improved functional outcomes. There are many combinations of medications, although there is uncertainty around which is the most effective.

It’s up to your doctor to decide which medication combination is best for you. In general, combination therapy is well tolerated but needs to be monitored closely for any increased side effects.

Conventional Synthetic DMARDs (csDMARDs)

Conventional DMARDs are made from synthetic chemical compounds with small molecules. Their relatively simple compound structures can be perfectly replicated by generic brands. They are also small enough to be processed through the digestive system, so they can be taken in oral form.

Conventional synthetic DMARDs are immunosuppressive medications that do not target specific parts of the immune system. Instead, they have a dampening effect on it. In Australia, the most common csDMARDs available to treat various autoimmune conditions include:

  • Methotrexate (Methoblastin®, Trexject®)
  • Hydroxychloroquine (Plaquenil®)
  • Leflunomide (Arava®, Arabloc®, Lunava®)
  • Sulfasalazine (Salazopyrin®, Pyralin®)


Methotrexate is considered the gold standard in terms of monotherapy treatment of autoimmune arthritis with a DMARD. It is generally the first choice of medication after diagnosis.

What do we already know about methotrexate?

Methotrexate works by blocking enzymes that help DNA (genetic material in the cells of your body) form or repair. This prevents some cells in your body from reproducing themselves. Experts believe that methotrexate also interacts with your immune system. Although it is not entirely clear how methotrexate works, it’s been proven to be effective in reducing swelling, pain and long-term damage to joints.

Methotrexate can be administered in several forms for autoimmune arthritis, usually on a weekly basis. Your rheumatologist may vary the dosage depending on the severity of your symptoms (up to the maximum recommended level for each form of administration).

It is available as a tablet, as a liquid that can be drawn and measured from vials and injected subcutaneously (just under the skin – like a flu shot) with a disposable syringe and as a pre-filled syringe (Trexject®) which can also be injected under the skin.

Some people have better results with subcutaneous injections as the medicine is absorbed directly into the bloodstream rather than passing through the digestive tract. Therefore it is often better tolerated by people who may have experienced an upset stomach when taking the tablet form.

What are the possible side effects of methotrexate?

It’s important to remember that most patients do not experience serious side effects, and for those who do have them, they may improve with time. Side effects are more likely to occur at higher doses and you should always consult your doctor if you think you’re experiencing any of these side effects.

  • Gastrointestinal problems, such as nausea, upset stomach or loose stools
  • Mouth ulcers
  • Hair loss
  • Abnormal liver function blood tests
  • Abnormal blood counts

Rare side effects include liver cirrhosis or scarring. This usually happens with patients who already have liver problems or are taking more medications that impact the liver. Lung problems also occur rarely, and typically only with patients who already have lung issues. Report any difficulty breathing or a cough that won’t go away to your doctor. Take these side effects very seriously.

People with liver disease may not be able to take methotrexate or require closer monitoring or lower dosing.

Increased skin sensitivity to the sun can also occur but may stop when the medication is stopped. Supplements like folic acid may help you manage these side effects. If regular folic acid doesn’t help, you may try another type called methylated folic acid. Talk to your doctor about getting methylated folic acid if you still get mouth ulcers, hair loss or just a “yucky feeling” from your methotrexate.

Do not plan to get pregnant while taking methotrexate. The Australian Rheumatology Association (ARA) recommends ceasing methotrexate one to three months before conception.

Certain antibiotics containing trimethoprim should not be taken with methotrexate.


Hydroxychloroquine is often used alone in mild autoimmune arthritis or in combination with other medications in people with more severe conditions.

What do we already know about hydroxychloroquine?

Hydroxychloroquine (Plaquenil) is an antibiotic used to treat malaria, but it also works to treat symptoms of rheumatoid arthritis, lupus and other rheumatic diseases. Although it is not a pain killer as such, it can reduce your joint pain and swelling in the long term. It may also help prevent joint damage or lower your risk of joint disability. For this reason, it is classed as a csDMARD.

We don’t really know why this medication works to control autoimmune arthritis symptoms or complications. One theory is that hydroxychloroquine interferes with communications between the cells of your immune system.

Your hydroxychloroquine dose will be based on your weight. The current maximum recommended dose is 5 mg/kg/day.

What are the possible side effects of hydroxychloroquine?

Most people tolerate hydroxychloroquine well. Some side effects include nausea and diarrhoea, but they may lessen over time or if you take your tablets with food. Less common side effects are rashes, changes in your skin’s pigment (like dark spots), changes to your hair (like thinning) or muscle weakness.

Although rare, hydroxychloroquine use could lead to damage of the cells in the back of your eye that detect light and colour. You’ll receive a specialised baseline eye exam when you start the medication. Later, you’ll follow up with your ophthalmologist as directed. The frequency of your eye tests may depend on your other medical conditions or if you have changes in your vision while taking hydroxychloroquine.

Hydroxychloroquine seems to be safe during pregnancy, but any time you are considering pregnancy (or if you have fallen pregnant) you should discuss all medications with your doctor.

Most vaccines can be given safely, but, once again, check this with your doctor.

Other rare side effects of hydroxychloroquine are:

  • Anaemia, especially in people with porphyria
  • Muscle weakness.


Leflunomide is used to treat some forms of moderate to severe autoimmune arthritis. It can lower joint damage and disability that these conditions can cause. It can also help ease your symptoms. It may be used alone or in combination with other DMARDs.

What do we already know about leflunomide?

Leflunomide blocks the development of certain cells in your immune system. By doing this, leflunomide works to suppress your immune system and reduce inflammation that causes pain, swelling and other symptoms.

The typical dose of leflunomide is one 20 mg tablet a day. Some people may take 10 mg a day, especially if the higher dose causes side effects. You should take your leflunomide with food.

It may take up to six to 12 weeks to notice a benefit from leflunomide. The full effect may take up to 26 weeks.

Leflunomide can interfere with other medications, such as phenytoin (for epilepsy), warfarin (a blood-thinning medicine) and tolbutamide (for diabetes). It is important to tell your doctor if you are taking other medications before commencing leflunomide.

While on leflunomide, you should not be given any “live” vaccines, such as those for measles, mumps and polio. Always check with your treating doctor before having any vaccines.

What are the possible side effects of leflunomide?

The most common side effect of leflunomide is diarrhoea. It often gets better over time. You can take antidiarrhoeal medicines to ease this side effect, or even lower your leflunomide dose.

Other side effects include nausea, indigestion, hair loss, mouth ulcers, easy bruising, stomach pain, liver toxicity or skin rashes. More rarely, this medication may lower your amount of blood cells or platelets or cause lung problems like a cough or shortness of breath.

One of the side effects of leflunomide, like methotrexate, is the potential for liver toxicity. So, you shouldn’t take certain medications while you take leflunomide and should avoid drinking alcohol. If you’ve had significant liver disease in the past, leflunomide may not be right for you.

As leflunomide suppresses your immune system, there is an increased risk of contracting some infections, especially the herpes zoster virus (chickenpox and shingles). Avoid contact with people who have contagious infections and contact your doctor if you show any signs of infection or fever.

While taking leflunomide, you must have regular blood tests to pick up any issues and make sure your liver function is healthy.

Leflunomide can be harmful to an unborn foetus. It can cause serious birth defects, so you should take extra precautions not to get pregnant while taking this medication. Because leflunomide can stay in your system anywhere from 10 weeks to two years, it is important to get a blood test to see if the medication is still in your blood before even trying to get pregnant.

Breastfeeding should be avoided as well unless leflunomide is completely out of your system. Men who take leflunomide should also use birth control to avoid getting their partner pregnant because of the birth defect risk.

If a woman wishes to conceive or a man wishes to father a child, in some situations, they may be able to take another medication to “washout” leflunomide from their system beforehand.

If an unplanned pregnancy occurs, cease leflunomide immediately and contact your rheumatologist to get expert advice on how to commence a “washout” treatment.


Sulphasalazine (also spelled sulfasalazine) is used to treat autoimmune arthritis symptoms like pain or swelling. Over time, it can help slow down the progression of your disease. It may be used alone or in combination with other DMARDs.

What do we already know about sulphasalazine?

Sulphasalazine is part of a class of medicines called sulpha medications. It’s a mix of salicylate, which is the main ingredient in aspirin, and a sulphur antibiotic-like component. Some people are allergic to all sulpha medications, so they can’t take sulphasalazine.

We don’t know exactly why sulphasalazine eases symptoms like pain, swelling or joint stiffness. It may prevent joint damage and over the long term, loss of your joint function.

Most people take two 500 mg tablets of sulphasalazine twice per day. Some people may start with a lower dose, such as one or two tablets per day, then build up to the normal dose. Some people may need six 500 mg tablets per day. It can take at least six weeks before symptoms start to improve.

You should take your sulphasalazine with food and a full glass of water to help ease stomach side effects. You shouldn’t crush or chew up your sulphasalazine tablets.

Sulphasalazine may interfere with other medications including warfarin, aspirin, some local anaesthetics and iron tablets. It is important to tell your doctor if you are taking other medications before commencing sulphasalazine.

Sulphasalazine should be safe to take during pregnancy. It may be necessary to take extra folic acid if you continue on sulphasalazine during pregnancy. Sulphasalazine has been associated with reduced sperm mobility, therefore men wishing to become fathers may need to consider stopping sulphasalazine three months before conception.

What are the possible side effects of sulphasalazine?

Most people have few side effects with sulphasalazine. The most common ones are nausea, upset stomach and headache. Usually, this gets better over time. You can take a coated sulphasalazine tablet that may be easier to digest.

Rarer side effects include headache, skin rashes, itching, mouth sores or liver or lung problems. If you get a severe rash, tell your doctor.

Sulphasalazine may make your skin more sensitive to sunburn, so wear a high SPF sunblock lotion or avoid getting too much sun. Some people who take sulphasalazine have orange-coloured urine or perspiration (or even contact lenses). While this seems alarming, it’s actually harmless. It will go away when you stop taking this medication.

While taking sulphasalazine, you must have regular blood tests to monitor your liver function (especially if you are also on methotrexate and/or leflunomide) and to monitor the medicine’s effectiveness.


Arthritis treatment information is also included in all editions of the CreakyJoints Australia Raising the Voice of Patients series. Learn more or download your free copy of A Patient’s Guide to Living with Rheumatoid Arthritis in Australia or A Patient’s Guide to Living with Axial Spondyloarthritis in Australia today.

For more information about biosimilars, the Therapeutic Goods Administration (TGA), Pharmaceutical Benefits Scheme (PBS) and much more, listen to the relevant episodes of our Patient PrepRheum podcast series or read the transcriptions attached to each episode.