Patients with SLE need more rest during periods of active disease. Researchers have reported that poor sleep quality was a significant factor in developing fatigue in patients with SLE. These reports emphasize the importance for patients and physicians to address sleep quality and the effect of underlying depression, lack of exercise, and self-care coping strategies on overall health. During these periods, carefully prescribed exercise is still important to maintain muscle tone and range of motion in the joints.

Nonsteroidal antiinflammatory drugs (NSAIDs) are helpful in reducing inflammation and pain in muscles, joints, and other tissues. Examples of NSAIDs include aspirin, ibuprofen (Motrin), naproxen (Naprosyn), and sulindac (Clinoril). Since the individual response to NSAIDs varies among patients, it is common for a doctor to try different NSAIDs to find the most effective one with the fewest side effects. The most common side effects are stomach upset, abdominal pain, ulcers, and even ulcer bleeding. NSAIDs are usually taken with food to reduce side effects. Sometimes, medications that prevent ulcers while taking NSAIDs, such as misoprostol (Cytotec), are given simultaneously.

Corticosteroids are more potent than NSAIDs in reducing inflammation and restoring function when the disease is active. Corticosteroids are particularly helpful when internal organs are involved. Corticosteroids can be given by mouth, injected directly into the joints and other tissues, or administered intravenously. Unfortunately, corticosteroids have serious side effects when given in high doses over prolonged periods, and the doctor will try to monitor the activity of the disease in order to use the lowest doses that are safe. Side effects of corticosteroids include weight gain, thinning of the bones and skin, infection, diabetes, facial puffiness, cataracts, and death (necrosis) of large joints.

Hydroxychloroquine (Plaquenil) is an antimalarial medication found to be particularly effective for SLE patients with fatigue, skin, and joint disease. Side effects include diarrhea, upset stomach, and eye pigment changes. Eye pigment changes are rare, but require monitoring by an ophthalmologist (eye specialist) during treatment with Plaquenil. Researchers have found that Plaquenil significantly decreased the frequency of abnormal blood clots in patients with systemic SLE. Moreover, the effect seemed independent of immune suppression, implying that Plaquenil can directly act to prevent the blood clots. This fascinating work highlights an important reason for patients and doctors to consider Plaquenil, especially for those SLE patients who are at some risk for blood clots in veins and arteries, such as those with phospholipid antibodies (cardiolipin antibodies, lupus anticoagulant, and false positive VDRL). This means not only that Plaquenil reduces the chance for reflares of SLE, but it can also be beneficial in 'thinning' the blood to prevent abnormal excessive blood clotting.

For resistant skin disease, other antimalarial drugs, such as chloroquine or quinacrine, are considered, and can be used in combination with hydroxychloroquine. Alternative medications for skin disease include dapsone and retinoic acid (Retin-A). Retin-A is often effective for an uncommon wart-like form of lupus skin disease. For more severe skin disease, immunosuppressive medications are considered as below.

Medications that suppress immunity (immunosuppressive medications) are also called cytotoxic drugs. Immunosuppressive medications are used for treating patients with more severe manifestations of SLE with damage to internal organ(s). Examples of immunosuppressive medications include methotrexate (Rheumatrex, Trexall), azathioprine(Imuran), cyclophosphamide (Cytoxan), chlorambucil (Leukeran), and cyclosporine (Sandimmune). All immunosuppressive medications can seriously depress blood cell counts and increase risks of infection and bleeding. Other side effects are peculiar for each drug. For examples, Rheumatrex can cause liver toxicity, while Sandimmune can impair kidney function. More recently, mycophenolate mofetil (Cellcept) has been used as an effective medication for lupus, particularly with kidney disease.

In SLE patients with serious brain or kidney disease, plasmapheresis is sometimes used to remove antibodies and other immune substances from the blood to suppress immunity. Some SLE patients can develop seriously low platelet levels, thereby increasing the risk of excessive and spontaneous bleeding. Since the spleen is believed to be the major site of platelet destruction, surgical removal of the spleen is sometimes performed to improve platelet levels. Other treatments have included plasmapheresis and the use of male hormones. Plasmapheresis has also been used to remove proteins (cryoglobulins) that can lead to vasculitis. Endstage kidney damage from SLE requires dialysis and/or a kidney transplant.