Drugs Used to Manage SLE

Daniel J Wallace MD
Clinical Professor of Medicine
Cedars-Sinai/UCLA School of Medicine
    
The management of systemic lupus erythematosus (SLE) is divided into four parts: physical measures, medication, counseling, and surgical procedures (e.g., joint replacement, splenectomy, biopsy). This monograph will review medication aspects for  treating the disease. However the reader shoud be cognizant that the other three
aspects of management play an important interactive role as well.
 
In considering therapies for SLE,
it should be noted that half of SLE
is organ threatening; which is
defined as involving th e heart,
lung,kidney, liver, central nervous system vasculitis, hemolytic anemia or thrombocytopenia. Half with SLE may have constitutional symptoms (e.g., fevers, swollen glands,  fatigue, weight loss), serositis (inflammation of the lining of the heart or lung known as pleurisy or pericarditis), swollen or painful  muscles or joints as well as rashes but their organs are spared.
Non-organ threatening disease is managed differently than its more serious counterpart and only has a 20% of disseminating to the organs. The risk of this spread is almost entirely limited to the first 5 years after diagnosis. Finally, medications are used to prevent certain aspects of lupus from manifesting themselves or involving specific organ systems and others are used to treat lupus subsets. With this in mind, we will now begin.
 
Therapies for non-organ threatening disease
 
The first line of treatment for SLE involves preventing sun induced damage to the skin. Ultraviolet radiation from the sun comes in several waves (UVA1, UVA2, UVB and UVC). Wavelengths of UVA2 and UVB are harmful in lupus and can lead to constitutional symptoms and promote inflammation. Agents which protect the skin are listed in Table 1. They should have a SPF (sun protection factor) of at least 15; if the SPF is too high they tend to dry, burn, sting or itch. Skin lupus rashes are managed with topical corticosteroids. A few rules of thumb: ointments are the best vehicle (80% absorbed), followed by lotions (50% absorbed) and creams (20% absorbed). Fluorinated steroids are more powerful than non-fluorinated ones (which include hydrocortisone creams available over the counter without a prescription). However, the former should never be used on the face for more than two weeks, since they are very powerful and can cause cutaneous atrophy which makes a rash look worse ( e.g., thinning of the skin allows one to see superficial vessels more easily). 
 
The second line treatment for SLE involves the use of nonsteroidal anti-inflammatory drugs, known as NSAIDs. None of these agents are approved by the Food and Drug Administration for the disease, even though 75% of lupus patients use them daily. NSAIDs are effective in alleviating headaches, muscle aches, joint aches, fevers, pleuritc or pericardial symptoms and reducing the size of swollen glands. Unfortunately, they do nothing to slow down the overall disease process and are viewed more as symptomatic therapy.  Traditional NSAIDs include aspirin (3 325 mg tablets every four hours while awake), ibuprofen (used as needed or in doses up to 3000 mg a day), or naproxen (usually as 500 mg twice a day). All these are available without prescription under names such as Advil or Aleve. Prescription traditional NSAIDs are listed in Table 2 with their dosing. In 1998, a selective form of NSAIDs, known as cox-2 inhibitors were introduced. This includes celecoxib (Celebrex). The principal concerns of using NSAIDs include potential stomach upset with or without ulceration, liver damage, rise in blood pressure, fluid retention, and kidney problems. 3% of all patients taking traditional NSAIDs and 1% taking cox-2 inhibitors on a daily basis are hospitalized for gastrointestinal bleeds every year. These agents may interfere with other drugs, especially blood thinners. Despite this, NSAIDs are usually quite safe and well tolerated. Your doctor may be consulted if you take an NSAID on a daily basis and he or she should obtain blood testing to monitor the safety of these agents every 3-4 months.
 
During the Second World War, 3 million Americans in the South Pacific theater took antimalarial drugs daily. It was serendipitously discovered that some of the soliders had rheumatoid or lupus related diseases and felt better when they took these agents. As our knowledge increased, it turns out that antimalarials have anti-inflammatory properties and act by raising the pH of the cell. When an acid cell is made more basic, certain autoimmune pathways are turned off. Hydroxychloroquine (HCQ, Plaquenil) is the only antimalarial approved by the FDA for use in SLE. 80% of patients with non-organ threatening disease who are given hydroxychloroquine are in remission after two years of therapy. HCQ is especially useful for fatigue, aching, and rashes and also has additional properties which are potentially important in SLE. These include lowering cholesterol, inhibiting platelets, decreasing sun sensitivity, and improving Sjogren’s syndrome symptoms (dry eyes, dry mouth). HCQ is generally very well tolerated. Approximately 10% develop a stomach upset, rash or headache within the first two weeks of use. To minimize toxicity, patients are often started on 200 mg a day for the first two weeks and the dose is raised to 400 mg afterwards. Some patients have fewer reactions when they use the brand name Plaquenil preparation. Since HCQ therapy can lead to pigment changes in the retina, toxicity from this affecting vision has been reported in 3% of those using the drug after 10 years, and in less than 1 in 10,000 cases in those using the drug for 5 years of less. All patients on HCQ should see an ophthalmologist at least once a year; these changes are reversible with the drugs’ discontinuation.  Occasionally, other antimalarial agents are used in SLE. These include chlroquine (Aralen) for serious lupus rashes and quinacrine (Atabrine) which is synergistic with HCQ, does not affect the eyes, and is helpful for fatigue and cognitive impairment associated with SLE.
 
Corticosteroids are used in high doses (>40 mg of prednisone a day) for acute flares short term or stable low doses for non-organ threatening disease in several circumstances. These include early disease when antimalarials have not had an opportunity to be effective for a few months, acute flares, or into a joint for localized inflammation. In doses for prednisone equivalent, stable dailiy doses of more than 15-20 mg are almost never required. If patients cannot be tapered within a short time to less than 10 mg of prednisone a day, the addition of a group of steroid-sparing agents can be considered. This is because prednisone can induce cataracts, glaucoma, ulcers, thinning of the bones, mood and behavior changes, edema, and lead to diabetes, hypertension and elevated cholesterol levels. The American College of Rheumatology has recommended that all patients who are going to take more than 5 mg of prednisone daily for 3 months have a baseline bone density evaluation and strong consideration should be given to the weekly administration of a bisphosphonate such as risedronate (Actonel) or alendronate (Fosamax).
 
Steroid-sparing agents for organ sparing disease include methotrexate, a rheumatoid arthritis agent administered weekly for individuals with prominent inflammation of the joints, leflunomide (Arava) which works in similar situations,  DHEA (compounded or at a health food store) for those with prominent fatigue or cognitive dysfunction, or azathioprine (Imuran) which is rarely used for severe rashes or joint manifestations. Refractory skin disease can be managed with retinoids (e.g., Accutane, Soriatene), antileprosy drugs (thalidomide, Lamprene, dapsone), topical immunophylles (e.g., Elidel, Protopic), or ultraviolet A1 light treatments. Some subsets of lupus may require special interventions. These include low dose aspirin for patients with antiphospholipid antibodies who are at risk for clotting, Salagen or Evoxac for those with symptomatic Sjogren’s syndrome and lupus. In addition to DHEA, other hormonal interventions have been utilized in  SLE such as danazol for low platelet counts, and bromocriptine (which lowers prolactin levels) for mild disease. Raynaud’s phenomenon can be ameliorated with calcium channel blockers (e.g., nifedipine) and topical nitroglycerine applications among other interventions.
 
Treatments for serious lupus
 
When SLE attacks the internal organs, practitioners usually prescribe prednisone in doses of 1 mg/kg/day for four to six weeks. Failure to do so often leads to compromised organ functioning. Very active disease can be managed with the use of “pulse steroids”, where doses of 1000 mg of intravenous methylprednisolone are given for 1-3 days. Many of these individuals also benefit from the addition of an immune suppressive regimen. For serious disease (e.g., aggressive proliferative nephritis, alveolar hemorrhage, mesenteric vasculitis), cyclophosphamide (Cytoxan, CTX) is usually given intravenously in monthly doses of 500-750 mg/M2. This agent has been available since the mid-1960s and is the most powerful weapon rheumatologists in practice have other than corticosteroids. CTX is associated with hair loss, low blood counts, altered immune responses, the development of blood in the urine in 10% of patients and nausea the day after administration. The most important factor deterring doctors from the more widespread use of CTX is its association with infertility in nearly all patients who are given the drug over the age of 30 and in half in their 20s. It is also a potential carcinogen. Aggressive efforts to search for safer alternatives has led to studies suggesting that mycophenolate mofetil (Cell Cept) may play a promising role in lupus nephritis. Although much safer than CTX, Cell Cept has little effects on other manifestations of SLE, such as arthritis. As mentioned above, azathioprine has been used as a steroid sparing agent for many years. Along with Cell Cept, it can be a successfully maintain remission in patients who have completed induction therapy with CTX. The transplant rejection drug, cyclosporine (Neoral) has found a niche and been determined to be effective in lupus patients with membranous nephritis and bone marrow failure.
 
Occasionally, other agents are used for serious lupus. These include chlorambucil, nitrogen mustard, 6-mercaptopurine, and intravenous immunoglobulin. A blood filtering treatment known as apheresis can be employed for rare complications of SLE such as thrombotic thrombocytopenic purpura, cryoglobulinemia, hypervisicosity syndrome, or alveolar hemorrhage.  Bosentan (Tracleer) and intravenous prostaglandin therapies lower pulmonary pressures in those with pulmonary hypertension.
 
Investigational therapies
 
Using very high doses of CTX is known as immune ablative therapy (a single dose of 13G; the usual dose is less than 1 G) and has been studied in small groups of patients with otherwise terminal disease. These doses can be given with or without a stem cell transplanatation. The use of “smart bombs” to manage SLE involves a family of drugs known as biologics. Though none are approved for SLE at this time, some of the agents being studied include rituximab (Rituxan), Lymphostat (an antibody to BlyS), and LJP-394 (an anti-anti-DNA).
 
Conclusions
 
Only aspirin, corticosteroids and HCQ are approved for use in SLE in the Untied States. Sun protective measures, the use of topical steroids for rashes and NSAIDs for constitutional symptoms is also an important part of managing SLE. Non organ-threatening disease can be ameliorated with HCQ, low dose corticosteroids, DHEA and methotrexate. Serious lupus is treated with high dose corticosteroids, and immune suppressive regimens which emphasize CTX, mycophenolate mofetil, and azathioprine. Biologic therapies are on the horizon and will no doubt have an important impact in the disease. Lupus International is committed to supporting research and increasing patient awareness relating to newer lupus treatments.