Until 40 years ago, systemic lupus erythematosus (SLE) was considered a generally fatal illness and few patients survived more than five years from the time of diagnosis. However, this situation has, thankfully, changed dramatically. In recent prospective studies, more than 80% of patients with SLE survived more than ten years, with many patients having a normal life expectancy.

Increased survival for SLE patients probably results from several factors, which include the use of high dose corticosteroids and immunosuppressive agents; the availability of newer more potent antibiotics; and the availability of dialysis and renal transplantation for end stage renal disease. In addition to better therapeutics, another important reason for the improved survival appears to be the ability to diagnose SLE in patients with milder forms of the disease and at earlier stages. Many SLE patients are young women with only arthralgias, fatigue, photosensitive skin rashes, mild anemia, leukopenia or thrombocytopenia, and serological evidence of systemic autoimmunity in the form of positive tests for anti-nuclear antibodies, anti-DNA antibodies and/or anti-Sm antibodies. The treatment of such patients is problematic since the side effects of long term corticosteroid and immunosuppressive drugs probably outweigh their symptomatic and physiological benefits. In this Cyberounds^®, we will review some of the treatment options that may be used to treat individuals with mild SLE. We will pay particular attention to newer approaches, which manipulate the hormonal status of the patients.

General Measures and Precautions

While only a minority of SLE patients actually manifest photosensitivity, it is still prudent to advise all patients with SLE to avoid excessive exposure to UV light. The use of sunscreens with an index of 25 or greater is recommended. For sexually active women who do not want to become pregnant, we are reluctant to use oral contraception since the estrogen in contraceptive doses has been frequently associated with disease flares. The lower doses of estrogen used in hormone replacement for menopausal women has not been clearly shown to be associated with a higher incidence of disease flares, but this is still an area of active investigation.

Many patients with SLE have a tendency to form endovascular clots in vivo. Most of these patients can be identified prior to their developing a clinically significant clot in either the venous or arterial system by the presence of anti-phospholipid antibodies. However, the titers of these antibodies may vary over time. We believe that it is not unreasonable to place all patients with SLE on anti-platelet therapy, such as low dose aspirin, even without a history of a clot, but especially those patients with a positive test for anti-phospholipid antibodies.

Even in the absence of clinical signs of nephritis, many patients with SLE may be hypertensive. It is extremely important to control the blood pressure in these patients so as to avoid additional damage to their kidneys and arteries. All of the commonly used anti-hypertensive agents have been used in SLE and there does not appear to be any of these drugs that is particularly more effective or more toxic. While hydralazine, which is currently not commonly used as a first line treatment for hypertension, can cause a lupus-like syndrome, this adverse reaction does not appear to be more common in patients with SLE. Patients with SLE have been shown to have a higher than expected prevalence of allergic reactions to sulfonamides and, therefore, these drugs should be used with caution in SLE patients.

Treatment

Nonsteroidal Anti-inflammatory Drugs (NSAIDS)

Arthralgias and myalgias can be frequent and early symptoms in SLE. It is generally recommended that NSAIDS be used to control such symptoms -- they are usually well tolerated. The newer COX2 selective agents might seem to be preferable in SLE patients because they are associated with a lower incidence of gastritis, ulcer and bleeding. However, these drugs can cause a decrease in renal function and hypertension similar to that seen with the non-selective NSAIDS and, therefore, should be used with caution in patients who have preexisting renal insufficiency, decreased renal blood flow or hypertension. In addition, patients with SLE may exhibit idiosyncratic reactions to NSAIDS, especially ibuprofen, manifested by fever and/or a picture of aseptic meningitis.

Anti-malarial Agents

Hydroxychloroquine (HCQ) is effective in the management of the musculoskeletal symptoms and many of the photosensitive cutaneous manifestations of SLE. An added benefit of HCQ is a lowering of serum cholesterol, which may be important in view of the increased incidence of atherosclerosis in patients with SLE who survive more than ten years. In one report, HCQ helped control the fibromyalgia symptoms commonly seen in patients with mild SLE. HCQ is usually very well tolerated when used in doses of six or less milligrams/kg/day. At these doses, the incidence of visual symptoms is quite low and can be completely avoided by ophthalmologic evaluations every six months. Other reactions to HCQ include erythema multiforme and a cardiomyopathy. Both of these reactions, while quite rare, can be confused with active SLE. Though other anti-malarial drugs, such as chloroquine and Atabrine, have been used in the treatment of rheumatoid arthritis, they have not been extensively studied in SLE.

Corticosteroids

Low dose corticosteroids are often effective in treating mild SLE to control the musculoskeletal inflammation, the fatigue, the occasional low-grade fever and some of the cutaneous features. While doses of less than 10 mg/day of prednisone or equivalent doses of other corticosteroids are usually well tolerated, their continued use over many years is likely to cause osteopenia. Therefore, most patients should be treated with a bisphosphonate and calcium and vitamin D. As noted above, estrogen therapy for the prevention and treatment of the osteopenia is relatively contraindicated. It is very important to taper steroids very slowly in patients with SLE in order to avoid disease flare. In patients on 10 mg or less per day, we usually lower the dose by a maximum of 10 per cent every 14 days.

In addition, there are features of SLE, such as serositis and seizures, which may be very symptomatic but do not carry any long-term increase in mortality or morbidity. The treatment of these manifestations of SLE usually requires intermediate doses of corticosteroids for short durations such as six weeks.

Emerging Therapies

Manipulation of the Hormonal Status

Clinical studies and bench research have suggested that female hormones are implicated in autoimmunity. In lupus patients, the female to male ratio is 9:1 during childbearing age but decreases after menopause. Evidence supporting a role for female hormones in the pathogenesis of SLE includes the observations that some female patients with SLE have abnormal estrogen metabolism, that male lupus patients tend to have decreased serum testosterone levels and that 16-26% of patients with SLE have increased serum prolactin levels. From studies with animal models of lupus, we know that treatment with estrogen and prolactin exacerbates lupus activity, while androgenic hormones have beneficial effects.

Over the past decade, there has been increasing interest in the immunomodulating functions of prolactin. It has been shown that lymphocytes have receptors for prolactin and can also secrete prolactin. These observations suggest that modulating prolactin may be a possible treatment for SLE.

A prospective, double-blind, randomized, placebo-controlled study(1) investigated the efficacy of bromocriptine, an inhibitor of prolactin secretion, as an adjunct to conventional therapy in SLE. Bromocriptine (2.5 mg/day) was compared to placebo in 66 lupus patients followed for 2-17 months (mean 12.5 months). Prolactin levels were significantly lower in the bromocriptine treated patients than in the control patients after 3, 6, 9 and 12 months of treatment. There was significant reduction in disease activity in the bromocriptine group, compared to control group, with significant SLEDAI (a validated scoring system for SLE activity) decrease and reduction in the mean number of disease flares/patient/month in the bromocriptine group compared to the control group (0.9 +/- 1.4 vs. 2.6 +/- 4.5, p<0.05 and 0.08 +/- 0.1 vs 0.18 +/-0.2, P<0.05 respectively). A recent randomized prospective blinded one-year study compared bromocriptine and hydroxychloroquine treatment in 28 patients with SLE.(2) Disease activity was suppressed equally with bromocriptine and hydroxychloroquine.

Decreased levels of testosterone and dehydroepiandrosterone (DHEA), a weak adrenal androgen, have been observed in male lupus patients, and studies of murine SLE show that androgens may reduce disease activity. These observations suggest a possible therapeutic role for androgens in the treatment of SLE. Several studies have demonstrated the beneficial effects of DHEA at doses of 200 mg/day on disease activity in lupus patients with mild to moderate disease.(3) In a placebo-controlled, randomized trial of 21 patients with severe active SLE, manifested by nephritis, serositis and/or hematological abnormalities, treatment with DHEA for six months, in addition to their regular therapy, had a small added benefit and was protective against corticosteroid-induced osteopenia.(4) DHEA is generally well tolerated, with acne, menstrual irregularities and hirsuitism being the most common side effects.

Concluding Perspectives

Systemic lupus erythematosus is an extremely variable disease. It is probably fair to say that no two patients present with the identical picture and, therefore, treatment should be tailored to the individual patient. The above review is meant to provide only guidelines and cannot take the place of careful follow up and rheumatology consultation.

It should always be remembered that patients who appear to have a mild form of the disease may develop more severe life-threatening features of SLE, for which the treatment may be quite different (see part 2 of this Cyberounds^®). Detecting these flares, before they have caused irreversible end organ damage and at a time when they are more amenable to treatment, requires careful clinical observation of patients. Clinicians will need to monitor both signs and symptoms of disease activity as well as appropriate serological tests, such as the titer of anti-DNA antibodies and the level of serum complement components. As patients with SLE live longer, treatment for some of the late sequelae of the disease -- atherosclerotic heart disease, osteoporosis, avascular necrosis of bone and cognitive loss -- present additional challenges for prevention as well as management.