Medications

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Steroids and Lupus

Glucocorticoids are natural steroid hormones produced in the outer part (cortex) of the adrenal glands. They are also referred to as corticosteroids or just steroids. For the treatment of lupus the word steroids means glucocorticoids and not anabolic steroids such as testosterone, a different class of medications used to increase muscle mass.

The major steroid produced in the body is cortisol (also called cortisone). Since its discovery in the 1940`s, this hormone has been used successfully to control inflammation in many diseases. Today, synthetic steroid medications (in pill, ointment and injectable form) are similar in structure and function to cortisol and are generally stronger. The most widely used steroids are Prednisone, Hydrocortisone, Methyl-prednisolone and Prednisolone.

The steroids, such as Prednisone are powerful anti-inflammatory medications. They directly stop the white cells, another part of our immune system, from exiting the blood vessels into areas of inflammation. Steroids also seal the walls of the vessels, further preventing the exit of harmful cells into the tissues. Steroids influence the activity of the lymphocytes, a key component of our immune system. These cells are responsible for much of the damage to the tissues in lupus patients. Finally steroids decrease the production of molecules such as prostaglandins that promote inflammation. Steroids work fast and cause significant improvement in patients’ symptoms. Steroids, especially in high doses, are generally used for severe forms of lupus. Patients with mild joint and skin disease should avoid steroid use, if possible. Steroids are essential in the treatment of kidney and brain/spinal cord disease. Serositis (inflammation around the lung and heart) is also very responsive to these medications. Sometimes abnormal lab tests coupled with early symptoms of a lupus flare will make the physician start steroid therapy in a lupus patient. This has been shown to actually prevent the full blown flare.

Topical steroid applications are widely used for the treatment of skin rashes. If these rashes are deep, steroids are injected inside the rash. Inflammation in a joint such as the knee can be effectively treated with an injection into the joint. Finally, management of the pregnant lupus patient is mainly with steroids, since most of the other medications used in lupus are potentially harmful to the developing baby. Steroids come in different formulations, such as pills, solutions for injections and skin preparations. They also come in eye drops, nasal sprays and inhaled forms.

The steroid that is used most commonly in lupus is Prednisone.

  • It comes in tablets of 1,5,10 and 20 milligrams (mg).
  • It is given once or twice a day and sometimes as much as four times a day. In some patients that have stable disease, it is preferable to give Prednisone every other day. This regimen can decrease the chance of getting side effects from the long-term steroid use.
  • Less than 10 mg a day is regarded low dose; 11 to 40 mg is medium; and more than 40 mg (up to 100 mg) is regarded as high dose.
  • It is a very important medication to control active lupus and sometimes it is even used to prevent a flare as mentioned above.
  • Since prolonged use in moderate or high doses can cause many side effects, an addition of a “steroid sparing” immunosuppressive medication can help the physician lower the dose of Prednisone. These medications include azathioprine (Imuran), methotrexate, mycophenalate (Cellcept) among others.

The injectable forms of steroids, referred to as “pulse steroid treatment, “can be used in very high doses for a few days for life or organ threatening disease. For example, acute brain disease can be treated with 1000 mg of Methyl-Prednisolone through the vein every day for three days.

These medications can prevent the body from producing cortisol, the natural steroid. When these medications are used for more than two weeks, the dose should be lowered slowly to give the body the chance to resume its normal production of cortisol. If the patient lowers the dose fast, or for any reason stops them, serious side effects, such as weakness, dizziness, muscle and abdominal cramps, low blood pressure, low blood sugar and low potassium may occur. If that happens the patient should be seen quickly by a physician and steroids given immediately.

The steroids, although extremely important in the treatment of lupus, have numerous and potentially serious side effects. Most problems arise with long-term, high dose steroid use.

Steroids can:

  • Increase appetite and cause weight gain.
  • Change the body shape (i.e. thin arms and legs but swollen face, upper back and abdomen). The face can take a more round, moon like shape.
  • Cause psychological problems, especially difficulty sleeping, irritability, mood swings and even depression.
  • Aggravate glaucoma; long-term use can cause cataracts.
  • Cause easy bruising of the skin and/or acne.
  • Cause muscle weakness and joint pains.
  • Suppress or permanently stunt growth in children, and delay the onset of puberty.
  • Increase the rate of infections, especially with very high doses.
  • Increase blood pressure, sugar, cholesterol and the lipids. This is particularly important in patients who also have high blood pressure and/or diabetes. These patients should be closely monitored while on steroids.
  • Cause the body to retain water and salt leading to high blood pressure and leg swelling. It is advisable to decrease the amount of salt in the diet while on steroids.

Long-term steroid use, especially in high doses, can cause serious side effects, such as:

  • Osteoporosis. This is a condition where the bones of the patient get thin, causing them to break. Osteoporosis is diagnosed by a bone mineral density scan or DXA scan, a form of x-ray that looks at the density of the hip and spine. To prevent osteoporosis, all patients on long term steroids should take 1500 mg of calcium and 400 IU of Vitamin D every day. These two supplements, although very important for protection of the bones of patients on steroids, oftentimes are not enough. If the DXA scan shows thinning of the bones, the patient should take medication to prevent further loss of bone mass, such as a biphosphonate (e.g. Fosamax or Actonel). Biphosphonates are often given to patients on steroids, especially older women and men, if they are going to be on moderate to high doses for long term to prevent osteoporosis, even if the DXA scan shows no osteoporosis.
  • Avascular necrosis (AVN) of the bone. Use of high dose steroids for a prolonged period of time in lupus patients is highly associated with AVN. When this happens the bone (more commonly the hip but also the knee, shoulder and other areas) is damaged and can cause significant pain. AVN is diagnosed through an x-ray or MRI of the affected area. Treatment is aimed at relieving the pain. Surgery is used in more severe cases.
  • Premature narrowing of the blood vessels (atherosclerosis). This condition is caused by cholesterol deposition and can lead to premature heart disease and strokes. It is very important for patients with lupus to have the other risk factors for heart disease, like cholesterol, blood sugar, and blood pressure, under control.

Steroids are extremely important for the treatment of lupus and can be life saving medications. They can cause many side effects though, particularly if used over a prolonged period of time in moderate to high doses. Generally, steroid use should be minimal and patients should always be vigilant about side effects. All patients on steroids should be aware of the danger of abruptly stopping these medications after using them for a long time.

Patients should also try to protect their blood vessels and bones to avoid atherosclerosis and osteoporosis, two of the most serious long-term complications of steroids. Keeping the blood pressure, blood sugar and cholesterol under good control, avoiding smoking and taking daily Calcium, Vitamin D and a biphosphonate, are simple measures to avoid serious problems.

Antimalarials & Lupus

Antimalarials were originally used for the treatment of a parasitic infection called malaria. The first antimalarial used in the treatment of lupus was quinine, more than 100 years ago. Currently there are three different antimalarials, all in pill form, that are used for the treatment of lupus in North America:

  • Hydroxychloroquine (Plaquenil)
  • Chloroquine (Aralen)
  • Quinacrine (Atabrine)

Hydroxychloroquine is, by far, the most prescribed antimalarial in the United States. It is thought to be the one with the least side effects.

Antimalarials decrease the inflammation by affecting cells of the immune system in multiple ways. There is some laboratory evidence that they may influence the production of the damaging auto-antibodies.

Many patients with lupus are very sensitive to sunlight, which can cause disease flares. Antimalarials have been found to enter cells in the skin and protect the body from the damaging effects of sunlight. This might be particularly important for lupus skin disease. They may have other beneficial effects, like lowering cholesterol (LDL-cholesterol) and making the blood slightly thinner by affecting certain blood cells calls platelets.

Antimalarials have been used in lupus patients to control skin rashes and joint symptoms. Although they are not very useful in treating more severe complications such as kidney disease, they have been shown to be effective in treating the following conditions:

  • Arthritis and joint pain.
  • Skin rashes, including the severe forms of discoid lupus and subacute cutaneous lupus. Half the patients will have improvement of their skin problems with the use of Hydroxychloroquine (Plaquenil). Chloroquine (Aralen) and Quinacrine (Atabrine) are probably stronger but may cause more side effects. Occasionally, doctors use combinations of these drugs to treat resistant skin rashes.
  • Inflammation of the lining around the heart (pericarditis) and the lungs (pleuritis).
  • Fatigue and fevers.
  • Maintenance therapy. Long term use of Hydroxychloroquine (Plaquenil) has been shown to prevent lupus flares.

Lupus patients tend to be on multiple medications to control their disease. Antimalarials have been safely used in combination with other medications such as steroids, blood thinners, non-steroidal anti-inflammatory medications and even chemotherapy drugs like Cyclophosphamide (Cytoxan), Azathioprine (Imuran) and Methotrexate. Patients on multiple medications should be closely monitored by a physician.

Traditionally, antimalarials have not been used in pregnant women, because of potential side effects that may affect the baby. Data from Europe and Canada do not show increased side effects in pregnant women who take Hydroxychloroquine (Plaquenil). Still, the fear of some adverse effects makes many patients and doctors reluctant to use them during pregnancy. The best approach is to weigh the risks of the medications with the risks of a lupus flare in an individual patient. These decisions should be made in discussion between the patient and the physician.

Generally, antimalarials have few side effects and most patients tolerate them well. They are often thought to be the safest medications used in the treatment of rheumatic diseases.

The most common side effects are in the skin, the stomach, the bowels and the brain.

  • Eye complications are feared the most but are very rare. They are generally very rare, but an ophthalmologist should monitor every patient who is taking these medications on a regular basis (every 6 -12 months).
  • Skin rashes (most of them allergic) and changes in skin color can occur. Quinacrine (Atabrine) can cause a yellow discoloration of the skin that is reversible. Hair loss and dry skin happen infrequently.
  • Gastrointestinal side effects are common, but most of the time mild. Patients can experience loss of appetite, nausea, upset stomach, bloating, stomach cramps and diarrhea. These drugs, however, do not cause ulcers or bleeding from the stomach.
  • Headaches, dizziness, nervousness, irritability, muscle aches and weakness can trouble some patients. Severe neurologic side effects, such as seizures and confusion, are rare. If they happen, they should be reported to the physician immediately. Rarely have these drugs, especially Chloroquine been implicated in nerve, muscle, and heart muscle toxicity.

Most of the above side effects are mild and can go away with a decrease in the dose of the medication. Local creams for the skin rashes and antihistamines for upset stomach can help.

Antimalarials can cause the inability to focus. Generally, this side effect is experienced early, within the first two weeks after the medication has been started. It is caused by dysfunction of the muscles that move the eyes. Very rarely, patients might experience double vision due to nerve dysfunction. These symptoms can go away without changing the dose of the medication.

Antimalarials can deposit on the retina, at the back of the eye. These deposits can affect the vision. Fortunately, there is an early stage that can be detected by an ophthalmologist. At this point, stopping the medication results in no further problems for the patient. If not attended to, this problem can cause serious visual problems, such as blurred vision, difficulty reading, flashing lights and blind spots. Chloroquine (Aralen) is probably the most toxic medication for the eyes. Quinacrine (Atabrine) does not seem to cause eye problems. The most commonly used Hydroxychloroquine (Plaquenil) rarely can cause this complication, especially at doses less than 6.5 mg/kg body weight. For most patients, that means that taking 400 mg a day or less of Hydroxychloroquine (Plaquenil) will rarely cause serious visual problems. Currently, we recommend that patients see an ophthalmologist once a year. The eye exam should include an examination of the retina in the back of the eye.

Hydroxychloroquine (Plaquenil) is the antimalarial used in most cases. Initially, it is started at a loading dose of 400 mg/kg a day (given as two 200 mg pills a day). Patients are kept at this dose for at least 6 months to a year. Most patients will then continue at the same dose, although there are patients who can be maintained on one 200 mg pill a day. Occasionally, the dose can be increased temporarily, usually for 2-3 months. This strategy is used to prevent or treat flares, such as worsening rashes in the summertime. This medicine must be taken regularly as ordered by your doctor in order for it to help you. It may take up to several weeks before any results are noticed and up to six months before the full benefit of these medications are felt.

Antimalarials are very safe medications that can control the joint pains and skin rashes caused by lupus and can help keep the disease in remission. The only serious side effect that needs to be considered is the eye problems they can cause. Every lupus patient taking these medications should have an eye exam by an ophthalmologist at least once a year.

Cellcept

Mycophenolate mofetil (CellCept®) is a drug that was developed to suppress the immune system, thereby preventing the rejection of transplanted organs. It is also used in lupus to slow down the immune system, particularly if inflammation threatens internal organs such as the kidneys.

Cellcept is an immunosuppressive agent that is similar to Azathioprine. Taken orally in doses of 1,000 to 3,000mg daily in divided doses, it has been shown to be as effective in some studies as Cytoxan for renal disease. Some lupus practitioners use it in lieu of Cytoxan or in addition to after several months of Cytoxan. Cellcept is usually well tolerated, but some users complain of gastrointestinal upset. Cellcept is contraindicated in pregnancy.

Antimetabolites and Anti-transplant Rejection Drugs

Medications under this heading include:

  • Azathioprine (Imuran) – a good steroid sparing agent for arthritis and organ-threatening disease activity. Imuran blocks the inflammation pathways and is FDA approved for Rheumatoid Arthritis. Imuran is used frequently as a compromise between potent chemotherapies and an ongoing requirement for high doses of oral steroids. It is generally well tolerated, with some patients experiencing stomach upset. Imuran does not alter fertility.
  • Methotrexate (Rheumatrex) – another good steroid sparing agent for lupus arthritis. Must be used carefully with kidney impairment, there is no evidence that it helps with organ-threatening disease activity. Low doses of Methotrexate decrease joint inflammation. It has little effect on organ-threatening disease activity, and if renal disease is present the doses have to be drastically reduced in to prevent a drop in blood counts.
  • Leflunomide (Arava) – helps lupus arthritis

Cytoxan

Belongs to a class of drugs known as alkylating agents, which were originally developed and are still used to treat some types of cancer. Cyclophosphamide is used in the treatment of lupus, systemic sclerosis (scleroderma), some forms of vasculitis, myopathies such as polymyositis and dermatomyositis, as well as some complications of rheumatoid arthritis.

Cyclophosphamide interferes with the deoxyribonucleic acid (DNA) in cells. This prevents cells from dividing, leading to cell death. Some of the cells affected by this medication are immune cells, which are involved in the development of autoimmune diseases such as rheumatoid arthritis, lupus, scleroderma or vasculitis.

Common side effects, which may be worse with the oral preparation, include nausea and vomiting. These symptoms can usually be controlled with anti-nausea medications. Hair loss can occur, but hair will grow back when the medication is stopped. Other common side effects include skin rashes. Cyclophosphamide increases the risk of developing some kinds of infections, especially herpes zoster, often referred to as “shingles.” These include nausea, vomiting, loss of appetite, mouth ulcers, fatigue, temporary hair loss, unusual bleeding or blood in the urine, shortness of breath, loss of menstrual periods, impotence, sterility, or signs of infection (such as increased temperature, sore throat, or flu symptoms).

Cyclophosphamide can cause infertility in both men and women, most often in older patients or those taking higher doses for long periods of time. Discuss this issue with your doctor before taking cyclophosphamide. Although women taking cyclophosphamide can stop having periods, they can still become pregnant so an effective form of birth control to prevent pregnancy should be used while taking this medication. Taking cyclophosphamide during pregnancy is very dangerous to an unborn child. Do not take this drug if you suspect you are pregnant. Cyclophosphamide causes birth defects. You must use an effective birth control method while you are taking this medication. You should consider pregnancy only after treatment has been stopped and your doctor says you are healthy enough to become pregnant.

Long-term therapy with cyclophosphamide may leave a woman unable to produce eggs, or a man unable to produce sperm. This means permanent sterility. If you want to have a baby in the future, talk to your doctor about the option of storing your eggs or sperm before beginning therapy.

Cyclophosphamide is broken down in the body into several other products. One byproduct known as acrolein can cause an irritation of the bladder, or “cystitis,” which may result in blood in the urine or scarring of the bladder. To avoid this common side effect, patients taking oral cyclophosphamide should drink plenty of fluids each day. Patients receiving intravenous therapy are sometimes given a medication called mesna (Mesnex) to help prevent bladder problems.

Cyclophosphamide increases the risk of a form of bladder cancer as well as other cancers, which can occur years after taking this medication. Individuals taking higher or longer-term doses of cyclophosphamide are at greater risk for developing cancers. Bladder cancer is the most common cancer related to cyclophosphamide, so your doctor will recommend periodic urine tests to screen for this.

Chemotherapy can be a scary-sounding word. Some rheumatologists instead use the word immunosuppressive”, cytotoxic” or steroid sparing” therapy. Essentially these therapies are used when serious organ-threatening disease is present and steroids alone are not sufficient to deal with the problem. They are also employed when a patient cannot tolerate high doses of steroids, because chemotherapies reduce steroid requirements. For severe kidney disease doctors usually give Cytoxan once a month for six months and then every two to three months until two years have elapsed.

NSAIDS (Non-Steroidal Anti-Inflammatories) American

NSAIDs, are a class of medications that work to decrease inflammation, pain and fever. Traditional NSAIDs include aspirin, ibuprofen (e.g., Advil, Motrin), naproxen (e.g., Aleve, Naprosyn) and many other generic and brand name drugs. The NSAIDs work by a different mechanism than steroid medications (such as prednisone) to decrease inflammation and pain. If the goal of taking the NSIAD is to suppress inflammation then it will need to be taken at higher doses and on a regular dosing interval. If it is to relieve pain and not necessarily inflammation, then often lower doses and an as needed dosing interval are sufficient.

NSAIDs are taken to relieve pain and reduce inflammation and fever. For chronic conditions such as rheumatoid arthritis, osteoarthritis, or lupus, these drugs are generally administered by a doctor in higher prescription doses and may be prescribed over a long period of time. Risks of all NSAIDs include, but are not limited to, stomach problems like bleeding and ulcer, high blood pressure, fluid retention, heart and kidney problems, and rashes.

You may use NSAIDs cautiously during pregnancy, but do not take them during the first 3 months of your pregnancy or just before delivery. NSAIDs appear in breast milk and should be used cautiously if you are breastfeeding. Some patients taking NSAIDs become more sensitive to sunlight. Use sun block and protective clothing; avoid exposure to sunlight.

Do not take more than the recommended dose.

Do not take NSAIDs with other drugs, including over-the-counter medications, without first checking with your nurse or doctor. Over-the-counter medications are medications that you can buy without a doctor’s prescription. Tell any nurse, doctor, or dentist who is taking care of you that you are taking NSAIDs for your lupus.

Since NSAIDs can cause stomach and intestinal upset and irritation, take them with food or after meals. You should also avoid alcoholic beverages, because alcohol can aggravate these stomach and intestinal problems. Check with your doctor for guidance on these issues.

Lupus Alliance of America, American College of Rheumatology, Daniel J Wallace, MD, Arthur Weinstein, MD, Vasileios Kyttaris, MD