Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often has a relapsing course. The primary thera- peutic approach, therefore, is to achieve and maintain adequate suppression of the disease without causing unacceptable drug side effects. In general, the approach to patients with SLE involves evaluation of specific symptoms and clinical findings to establish the type and extent of organ involvement and overall disease activity, aided by labo- ratory tests to contribute to the overall therapeutic plan. Table 1 groups disease manifestations into three broad categories based on primary treatment modality used for initial management.

Table 1 (See Table 1)

Adapted from Decker JL Management. In Schur PH (ed): The Clinical Management of Systemic Lupus Erythematosus.
Orlando, Grune and Straton, 1983, p 259.

Fever, joint pain (arthralgias), arthritis, and serositis (pleurisy or pericarditis) can often be managed effectively by non- steroidal anti-inflammatory drugs (NSAIDs)
alone. Many different NSAIDs are available, ranging from aspirin to the non-acetylated aspirin derivatives (Trilisate, Disalcid, Salsalate), which have lesser GI or kidney side
effects, and do not affect bleeding as can be seen with regular dosing of aspirin. There are also a variety of non-aspirin anti-inflammatory drugs such as Ibuprofen, Naproxen,
Diclofenac, Sulindac, etc., which can provide similar anti-inflammatory benefit with less frequent dosing and side effects.

Commonly Used Nonsteroidal Anti-Inflammatory Agents

Acetylated Salicylic Acids

Non-Acetylated Salicylic Acids

Non- Steroidal Anti-Inflammatory Agents

Experience with the specific drug, adverse reactions, patient tolerance and compliance in dosage and cost, are all relevant for the choice of NSAID. In general, in the absence of side effects, an NSAID should be continued at least 2-4 weeks at maximum dosage before switching to a second agent due to lack of benefit.

Although NSAIDs are usually well- tolerated, they are associated with a range of potential side effects or toxicities. Gastrointestinal complaints are the most common and potentiation of peptic ulcer is of concern. Special effort should be made to administer these drugs after eating, and medications helpful in protecting the stomach can be administered in patients susceptible to this risk. Mild irritation of the liver, with resul- tant elevation of liver enzymes can occur, but is generally not associated with any chronic irreversible damage if detected and discontinued. Renal side effects raise a greater concern, particularly in patients with nephritis. These can include elevation of blood pressure, edema formation, elevated potassium, or decline in renal function. Therefore, although these side effects are uncommon, they do indeed require monitoring by the physician to detect abnormalities that the patient may be unaware of, with routine laboratory testing.

Additionally, it should also be emphasized that over-the-counter derivatives of aspirin and ibuprofen fall into this category; their regular use should be brought to the attention of the physician and should never be mixed or taken in addition to the NSAID prescribed by the physician. Rather, aceta- minophen derivatives, (i.e., Tylenol), can be safely taken concomitantly with NSAIDs for added pain relief. Anti-malarial drugs (hydroxycholoro- quine, chloroquine, and quinacrine) are most effective for the management of cutaneous features of lupus. With proper ophthalmologic follow-up and careful attention to dosage recommendations based on ideal body weight, anti-malarials are among the safest oral medications available for treatment.

Improvement in skin lesions may be evident as early as 1-6 weeks after beginning treatment, and agents have been used alone or in combination with each other. Also, substitution of one anti-malarial for another is often effective. Once complete healing of skin lesions has occurred, the dose should be slowly decreased, if possible, to the lowest effective maintenance dose, which may be as little as several tablets weekly. But due to the high rate of cutaneous relapses and the extreme safety of low-dose therapy, an anti-malarial should be given indefinitely to patients with previously severe or extensive skin disease that has improved.

Dosage Guidelines for Anti-Malarial Therapy (See Table)

* Reference 78 and 79.
† Based on ideal body weight. If this low dose is never exceeded, then preretinopathy is rare, and retinopathy should
never be seen.78,79,108.
‡ Based on actual body weight. If this dosage is exceeded, preretinopathy develops in an unknown significant number
of patients and, if drug therapy is not continued, preretinopany, may 7 .
progress to retinopanty. This process may be
42 82,9
more common in patients taking chlroquine at this dosage.

Systemic manifestations also respond to anti-malarials. Joint pain and arthritis tend to improve over several weeks of therapy. There may also be variable effectiveness in relief of fatigue, muscle discomfort and pleurisy chest pain. Flares appear to occur with lesser frequency, and the amount of steroids necessary to control disease activity may be lessened with concomitant use. An added benefit of Plaquenil use at a dosage of 400 mg. daily may be its association of lower cholesterol levels in lupus and rheumatoid arthritis patients. This may serve as a mechanism to reduce elevated triglycerides, cholesterol and low-density lipoprotein levels observed in lupus patients treated with steroids. More common side
effects include gastrointestinal symptoms, which are minimized on divided or bedtime dosage, and dermatologic manifestations (itching, rashes, and bluish-black pigmentationchanges). Retinal toxicity is associated with high-dose hydroxychloroquine or chloroquine therapy (not quinacrine).

Pre-retinal changes can be detected by regular ophthalmologic follow-up and are reversible on drug discontinuation with the exception of macular pigmentation, which does not affect vision and is not progressive in absence of the drug. Retinopathy, on the other hand, represents irreversible damage to the retina and macula, but is preventable with low-dose therapy and regular eye exams every six months. Corticosteroid given orally or intravenously (bolus therapy) are often necessary for more serious organ involvement. Topical preparations are appropriate treatment for dermatologic manifestations and Prednisone is the most commonly used oral corticosteroid. Intravenous methylprednisolone pulse therapy (high-dose) has come into widespread use in the last decade for lupus nephritis and other serious nonrenal manifestations, such as hemolytic anemia, central nervous system inflammation (cerebritis), life-threatening lowplatelet counts, and severe pleuropericarditis when oral steroids are not effective.

The IV approach may enable a more rapid, more sustained response, with fewer or only transient side effects (elevated blood sugar, hypertension, potassium abnormalities, etc.). Side effects of chronic Prednisone administration such as moon faces, truncal fat redistribution and skin and capillary fragility are not encountered. Susceptibility to infection is always a concern in chronic steroid use. Immunosuppressive drugs used in treatment of SLE include azathioprine (Imuran), alkylating agents (nitrogen mustard, cyclophosphamide, and chlorambucil). Methotrexate has been used sparingly, but recent studies suggest it may have a role given orally weekly It is beneficial especially in the setting of multi-joint inflammation and for reduced high-dose Prednisone administration.

Indications for use include

1) life-threatening disease unresponsive to high-dose Prednisone and IV bolus therapy;
2) active major organ involvement resistant to high-dose Prednisone for 4-6 weeks;
3) active major organ involvement which recurs with reduction of corticosteroid dosage or requires unacceptably high steroid maintenance dose;
4) intolerable corticosteroid toxicity (glucose intolerance requiring insulin, recurrent infections, significant hypertension, osteoporosis with vertebral compression fractures, etc.);
5) active major organ involvement in a patient who already has contradications to high-dose steroids; and
6) certain active organ manifestations that respond better to combination treatment with steroid and immunosuppressives. Cyclophosphamide (Cytoxan) has been the most extensively studied alkylating agent in SLE. Benefit in severe lupus nephritis has been established, often in combination with corticosteroid particularly with monthly intravenous administration, since daily oral administration is associated with greater side effects of infection, bladder toxicity and complications, malignancy, and sterility.

Azathioprine (Imuran) is also used in SLE patients whose disease is resistant to steroids or to enable steroid dosage reduction. Overall benefit combined with Prednisone in lupus nephritis has been met with mixed results but may be beneficial in patients with antimalarial resistant discoid lupus. There are fewer major side effects associated with azathioprine as compared to cyclophosphamide, but those most important include infection, liver toxicity, low white blood cell or platelet counts and malignancy.

New concepts in treating SLE continue to evolve. Plasmapheresis or plasma exchange is still considered experimental by many and reserved for the acute management of life threatening disease or severe major organ disease unresponsive to therapies previously discussed. In this process, plasma is removed from intravascular circulation by a special separation process with subsequent return of important cellular components to the bloodstream. This therefore allows the depletion of circulating immune complexes, antibodies and active complement components involved in perpetuating the harmful immune destructive process involved in the damage of internal organs. The most consistent and prolonged responses appear to occur in patients whom plasmapheresis is combined with steroids and an immunosuppressive drug. Dramatic effects have been observed in life-threatening steroidresistant circumstances, including lupus nephritis, lung hemorrhage, removal of cardiolipin antibodies (elevated levels predispose to arterial and venous clots). Although it is generally considered a safe procedure clinically, significant infections can occur (12 percent incidence).

Intravenous immunoglobulin (IVIG) is another experimental therapy used for serious end-organ circumstances. Benefit has been seen in some case reports of severe lupus nephritis, severe refractory thrombocytopenia (low platelets) and, in general, aspects of SLE. Other studies have been less encouraging. Hence, though expensive, it may be used in very selective situations. Cyclosporine, an immunosuppressive drug used in transplant patients, has also been found to have possible usefulness for treating lupus nephritis. Toxicity to the kidney, however, may limit its benefit and warrants further need for multicenter, doubleblind studies. Likewise, total lymphoid irradiation, successful in treating Hodgkin’s disease, has also shown benefit in intractable kidney disease; risk of infection is similar to that seen with immunosuppressives.

Sex hormone manipulation may also be a mechanism of retarding disease in humans. Since 90 percent of lupus patients are females aged 13-40 yrs., mild androgenic compounds such as Danazol and more recently DHEA (Dehydroepiandrosterone) have been tested and proven beneficial in mice with lupus nephritis. Danazol has proven effective in controlling immune thrombocytopenia and severe hemolytic anemia in human patients failing to respond to steroids, IVIG, spleen removal and immunosuppressives. In a recent study, DHEA was beneficial in two-thirds of a group of 50 patients given treatment for up to 12 months. Side effects included acne, facial-hair growth and irregular menstrual periods. An entirely new approach with LJP 394 Toleragen is currently in clinical trials. It appears to be a safe therapy that aims to educate the immune system to cease making potentially harmful anti-DNA antibodies. It requires weekly injections and is still experimental. Finally, there appears to be promises in the approach of cutaneous lupus with retinoids. Use of istretinoin (Acutane) and etretinate (acitretin) demonstrate beneficial results when given orally, with reduction of lesions refractory to prior use of steroids and antimalarials.

In summary, many patients with SLE can be treated effectively with NSAIDs and antimalarials without ever having to take steroids at all or for any prolonged length of time. Conversely, some patients with life-threatening disease, active major organ disease, or intolerable steroid toxicities should be given immunosuppressive drugs, plasmapheresis and/or other therapies in addition to corticosteroid early in their disease course, before permanent end-organ damage occurs and before serious complications of prolonged, daily high-dose steroids develop. Hopefully, future testing will help us define, at disease onset, those patients destined to have severe disease and allow a more rational approach with diseasemodifying therapy to maximize the successful treatment of SLE.