Family doctor

Disease Modifying Medicines for Rheumatoid Arthritis:

There are a number of medicines used for Rheumatoid Arthritis that are not steroids like prednisone, or the typical anti-inflammatory (NSAID) medicines (see article on NSAID). These are called disease modifying antirheumatic drugs, or DMARDs, and they include gold and transplant medicines.

These medicines are becoming more commonly used early in the treatment of arthritis, usually depending on how bad the arthritis seems to be. It is thought that starting these medicines early may improve the way the disease develops. However, there have not been very many trials in this area, and it is still uncertain exactly when is the best possible time to start them.

Unlike anti-inflammatory medicines, they are not pain-relievers but instead can slow the progression of the disease. These medicines can sometimes have bad side effects, and often will need frequent blood checks. For some of the medicines, the dose used in rheumatoid arthritis is much lower than the dose used for other conditions that can mean side effects are less than usual with the medicines. These medicines are more expensive than other arthritis treatments, especially if the blood tests are also considered.

Use: Rheumatoid Arthritis

These medicines are used for a variety of other diseases or conditions, not just arthritis. For example, azathioprine and cyclosporin are used in transplants (e.g. kidney or heart transplants) so that the body can function with an organ from another person. Penicillamine is used in lead poisoning, and sulphasalazine is used in ulcerative colitis. It is strange to think that a group of medicines with such a variety of uses can be helpful in rheumatoid arthritis.

Medicines in this group include:

• Gold preparations: Auranofin (Ridaura tablets) or Aurothiomalate (Myocrisin injection)
• Medicines used for malaria: Hydroxychloroquine (Plaquenil)
• Medicines that suppress the immune system: Azathioprine (Imuran, Thioprine), Methotrexate (Methoblastin, Ledertrexate, Emthexate), Cyclosporin (Sandimmun, Neoral), Cyclophosphamide (Cycloblastin, Cytoxan, Endoxan)
• D-Penicillamine (D-Penamine)
• Sulphasalazine (Salazopyrin)

Not all of these medicines will be registered in every country for rheumatoid arthritis.

Most of these medicines are not considered to be pain-relievers or anti-inflammatories, although sulphasalazine has some anti-inflammatory effects. It is not known exactly how these medicines work, although there are a few ideas. They take some time to make you feel better, perhaps a few weeks or months after starting the medicine.

These medicines cannot fix damage already done but may help to slow the disease progress. Sometimes two of these medicines might be used together. If one of the medicines has given you side effects or if it hasn't seemed to work for you after perhaps six months, another one might be used instead. Even with good results, the effect may start to wear off after a couple of years of treatment, so then another one is tried.

Cautions:

Pregnancy and breastfeeding must be avoided while having treatment with these medicines.

The cautions vary with the medicines as follows:

Gold therapy

• Do not use in: kidney disease, severe liver disease, allergy to gold or other ingredients, a history of severe blood disorders. There are several other uncommon diseases that a doctor will also watch out for.
• Blood tests should be done regularly, including prior to treatment.
• Take special care in kidney or liver disorders, inflammatory bowel disease, someone with general history of allergies, previous serious side effects with gold.

Hydroxychloroquine (Plaquenil)

• Do not use in certain eye conditions (maculopathy), allergy to this or similar medicines.
• Do not use long term in children.
• Regular blood tests are recommended.
• Take special care in patients with severe stomach or intestine problems, nerve/brain problems, blood disorders, porphyria or psoriasis.

Sulphasalazine (Salazopyrin)

• Do not use in blood, liver or kidney problems, porphyria, a history of allergies or rashes to sulphonamides (e.g. co-trimoxazole), diabetes tablets and thiazide diuretics.
• Do not use if you are extra sensitive to salicylates, e.g. aspirin, or if you have blocked intestine or urine passages.
• Do not use in children 2 years or younger.
• Sore throat, high temperature (fever), small haemorrhage in the skin (purpura) or yellowing of skin may be symptoms of serious side effects, so need to be seen by a doctor urgently.
• Special care should be taken in people with G6PD Deficiency, and people with general allergies (atopic).
• Blood counts are recommended before and during treatment.

Penicillamine (D-penamine)

Do not use in people with lupus erythematosus, or previous blood problems with penicillamine. Best avoided if kidneys are not working well. Occasionally people who are allergic to penicillin may be allergic to penicillamine.

Methotrexate (Methoblastin, Ledertrexate, Emthexate)

• Do not use for rheumatoid arthritis if extra-sensitive to methotrexate, or if the patient has low kidney function, liver problems, alcoholism, serious infections, stomach ulcers, ulcerative colitis or bone marrow problems.
• This medicine should only be used by, or under the guidance of, a specialist and requires a close watch on the patient for side effects, including regular blood tests and liver and kidney function.
• Watch carefully for signs of infection and see a doctor quickly if you think you may have an infection. Check with a doctor if you have any signs of infection, ongoing cough or if you have severe, ongoing vomiting or diarrhoea.
• Avoid dehydration or acid urine.

Cyclosporin

• Do not use if allergic to this medicine.
• Frequent blood pressure checks, and various blood tests are recommended, including checking on the health of the liver and kidneys and checks of the amount of cyclosporin in the blood.
• It is important to avoid too much potassium (in bananas and apricots for example).
• Vaccinations may be less effective than usual when taking cyclosporin, and it is important to avoid live attenuated vaccines.
• Cyclosporin should not be used for arthritis in people with kidney problems, high blood pressure that is not under control, infections that are not under control or any kind of cancer.

Azathioprine

• Do not use if allergic to this medicine or other ingredients in the tablets, or in patients with Lesch-Nyhan syndrome.
• Care if allergic to 6-mercaptopurine.
• Regular blood checks may be necessary.
• Care if kidney or liver problems.
• Response to vaccines may be reduced. Do not use with live vaccines.

Cyclophosphamide

• Do not use if cystitis with blood, infection, certain problems from radiation or severe problems with the bone marrow. Contact your doctor promptly if you have signs of infection.
• Careful monitoring is required including blood tests and perhaps urine tests. Do not get dehydrated while using this medicine. Care in people with some heart problems, diabetes, or porphyria.

Side effects:

Each medicine is different with respect to possible side effects. It is best to discuss with your doctor or pharmacist possible side effects with the medicine you are taking.

Gold: Watch especially for rash, diarrhoea or loose stools, sometimes with a feeling of stomach upset are common, but don't usually stop the treatment. Kidney problems. Some blood problems can occur which is why the regular blood tests are important. However, if you feel unwell or get unusual spots on the skin, seek medical help promptly and always let the doctor know you are taking gold therapy. Headache and dizziness are uncommon.

Hydroxychloroquine: Nausea, diarrhoea, rashes, hair loss and stomach ache may occur in 1-10% of people using this medicine. Other side effects are less common, but include possible eye problems such as changes to the cornea, blurred vision, halos around lights and wanting to avoid strong light. Problems with the retina can occur and six-monthly eye examinations are recommended to catch these problems early. The risk of retinal problems is increased with higher dose and longer-term use. Blood disorders are rare, but check immediately with a doctor if sore throat, fever and/or rash occur. Vertigo, ringing in the ears, muscle weakness and headache can also occur. Liver problems are very rare.

Sulphasalazine: Sore throat, high temperature (fever), small haemorrhage in the skin (purpura), swelling of the face or around the eyes, or yellowing of skin may be a sign of serious side effects, so need to be seen by a doctor urgently. Nausea, vomiting and reduced appetite are common, but can be reduced by using the specially coated formulation designed to dissolve only after leaving the stomach (enteric). Itchy red skin, headache, sperm changes (sperm goes back to normal after stopping the tablets), and increased body temperature can also occur. Blood disorders, kidney and liver problems and serious skin problems have been reported very rarely. Dizziness, ringing in the ears, stomach pain and some other side effects can be related to the dose taken, so can reduce if the dose is reduced. May reduce folate (folic acid). Can colour urine, sweat, tears and contact lenses orange.

D-penicillamine: Side effects are common including nausea, vomiting, reduced appetite, mouth ulcers and change in taste. Skin rashes, protein in urine, blood disorders, breast enlargement (men and women), liver and kidney problems are also possible side effects (some of these are uncommon). May slow the healing of skin. Check immediately with a doctor if sore throat, fever, yellowing of skin or skin rash occur.

Methotrexate: Because the medicine affects tissues that are quickly replenishing themselves, methotrexate can have side effects on normal body tissues that come into that category, e.g. bone marrow, or food passages including the mouth. Common side effects include nausea, stomach upset, effects in the mouth, and reduction in white cells in the blood. See a doctor quickly if you have any signs of infection, any lung symptoms such as ongoing cough, tight chest or chest pain, or vomiting or diarrhoea that is severe and ongoing. Nausea, vomiting, diarrhoea, skin rash, itching and redness, increased skin sensitivity to the sun, hair loss, headache, back pain, kidney problems, cystitis, fertility problems, and a variety of other effects can occur. Some of the side effects are related to dose, and the dose for rheumatoid arthritis is usually low.

Cyclosporin: The more common side effects include: hair growth, tremor, kidney and liver effects, high blood pressure, tiredness, mouth problems, stomach upset, reduced appetite, vomiting, stomach pain, diarrhoea, burning sensations in the hands and feet (first week of treatment). Less common side effects include headache, skin rash, weight increase, and painful periods or less frequency of periods. Rarely blood disorders can occur. There are other unusual effects for this medicine that your doctor or pharmacist will be able to tell you about.

Azathioprine: Possible signs of hypersensitivity include dizziness, nausea, vomiting, diarrhoea, fever, rash, sore muscles and joints, kidney problems, rigidity and low blood pressure. If hypersensitive, azathioprine is stopped immediately. The bone marrow can be affected so signs of infection should be checked with the doctor quickly. Hair loss is possible. Stomach upset can be a problem if the medicine is not taken after food. Uncommon effects include pancreatitis, liver problems, and inflammation of the lungs.

Cyclophosphamide: Bone marrow effects, and therefore blood disorders. Nausea, vomiting, reduced appetite, stomach discomfort, diarrhoea, mouth ulcers and pain on urination with blood cells in the urine may be more common effects. Liver and kidney effects, hair loss, skin rash, increased pigmentation in the skin. Some effects only seem to be related to high doses and use in transplants and cancer. Effects on sperm possible. Change in periods including stopping of periods. Headache, dizziness, tiredness, myxoedema (low thyroid, skin effects), slower wound healing, short-sightedness that comes and goes.

There may be other side effects, so if you have any unexpected symptoms while taking this medicine, tell your doctor or pharmacist.

Interactions:

• Never take another medicine or remedy - prescription medicine or a remedy from a pharmacy, health shop or supermarket, without checking with your doctor or pharmacist if the medicine/remedy can safely be taken with your arthritis treatment.
• Gold: Take especial care with medicines that can be hard on the kidneys or the blood, and medicines that are very protein-bound or those that speed up or slow down the movement of food through the stomach and intestines.
• Hydroxychloroquine: Digoxin and monoamine oxidase inhibitors (e.g. tranylcypromine).
• Sulphasalazine: Possible interactions include anticoagulants (e.g. warfarin), methotrexate, sulphonylurea diabetes medicines, urine acidifiers, phenylbutazone, indomethacin, sulphinpyrazone, salicylates (e.g. aspirin), penicillins, some local anaesthetics, and digoxin. Do not take antacids (indigestion remedies) at the same time.
• Penicillamine: Iron, other metals, antacids (indigestion remedies) and food should not be taken within 2 hours of penicillamine. Insulin-using diabetics may have a different need for insulin while using pencillamine.
• Methotrexate: Antibiotics may reduce the amount of methotrexate taken up by the body when both are given by mouth. Salicylates (e.g. aspirin), sulfonamides (e.g. co-trimoxazole), sulfonylurea diabetes medicines, phenytoin, phenylbutazone, aminobenzoic acid, penicillins, tetracyclines, probenecid, chloramphenicol, cholestyramine, NSAIDs (e.g. diclofenac, indomethacin, ketoprofen, azapropazone), pyrimethamine, trimethoprim, folic acid (in some multivitamins; avoid), L-asparaginase, etretinate, nitrous oxide anaesthesia, amiodarone, PUVA treatment, live vaccines (do not give), packed red blood cells.
• Cyclosporin: Take special care if using cyclosporin with other medicines that can have bad effects on the kidney, e.g. ciprofloxacin, melphalan, trimethoprim, non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac). Interactions include lovastatin, colchicine, ketoconazole, erythromycin (and other antibiotics in the same class), doxycycline, oral contraceptives, propafenone, calcium channel blockers (e.g. diltiazem, nicardipine, verapamil), nifedipine, barbiturates, carbamazepine, phenytoin, metamizole, rifampicin, nafcillin, prednisolone, grapefruit and its juice.
• Azathioprine: Allopurinol, oxipurinol, thiopurinol, co-trimoxazole, captopril (possibly), cimetidine, indomethacin. Do not use live vaccines.
• Cyclophosphamide: If cyclophosphamide is used with other drugs that suppress the immune system or are cytotoxic, some side effects may be more severe than for either medicine alone. Possible interactions include: allopurinol, prednisone, barbiturates and some other epilepsy medicines, chloramphenicol, sulphaphenazole, chloroquine, imipramine, phenothiazines, potassium iodide, vitamin A, digoxin, succinylcholine (an anaesthetic), indomethacin, anticoagulants (blood-thinners, e.g. warfarin), insulin, diabetes medicines, suxamethonian. Laboratory values can be affected by cyclophosphamide including candida, mumps, trichophyton, tubercolin and the Papanicolau test.

Patient information:

• Follow the instructions on the label of the medicine or as directed by your doctor.
• Keep these and other medicines well out of the reach of children. Dispose of any left over medicines carefully.
• Seek prompt medical attention for anything that may be a side effect, especially infection, rash, unusual bleeding or bruising, yellowing of the skin.
• Do not take more of the medicine than the doctor has prescribed.
• Do not take other medicines (including medicines without prescription from the pharmacy or supermarket, or your cupboard at home - even aspirin!) without checking with the doctor or pharmacist that they are safe with your medicine for rheumatoid arthritis. Do not take any alternative remedies with these medicines without first checking with your doctor or pharmacist - some may interact.
• Your doctor will be able to advise you on particular symptoms for your medicine that may indicate a serious side effect, and what to do if you get these symptoms.
• Make sure you have all the blood tests or urine tests the doctor asks you to have - these can show serious side effects early.
• Do not give these medicines to anyone else to take.
• If you are considering having a vaccination, talk to your doctor about whether it should be used with your medicine, and if so, if it will be effective enough.
• Penicillamine increases the need for pyridoxine (vitamin B6) and 25mg per day may be useful.

Please note: when discussing a number of different medicines, there is a limit to how much information can be given. Talk to your doctor for information about your specific medicines.