Systemic Lupus Erythematosus: Which Drugs and When?

Ronald F van Vollenhoven

Disclosures

Int J Clin Rheumatol. 2014;9(4):385-394. 

In This Article

Long-term Treatment of Nonrenal SLE: Maintenance Therapy

When the flare is under control and glucocorticoids are being tapered there is often a major risk for relapse if no other therapy is initiated. For this reason, many clinicians will start longer-term, maintenance therapy when the patient is being treated for a disease flare or shortly thereafter. The drugs most commonly used in this setting are antimalarials and conventional immunosuppressives (Table 3).

Antimalarials

The clinical efficacy of antimalarials was first noted during the Korean War in soldiers with SLE: skin manifestations, and to some extent arthritis, responded well to standard antimalarial therapies. Later experiences led to the wide-spread use of chloroquine for cutaneous lupus and even for systemic manifestations, and later still hydroxychloroquine (HCQ) became the preferred antimalarial on account of somewhat lower risks, and most clinical studies have been done with HCQ. Quinacrine is also used in some parts of the world. Antimalarials have a slow onset of action, taking weeks or months to provide a noticeable benefit for the patient. One of the most often-cited studies on HCQ was designed to demonstrate that the antimalarial prevents SLE flares.[7,8] In this study, a withdrawal design was utilized, whereby patients on a stable dose of HCQ were randomized to discontinue the drug or not. And indeed, those who did discontinue had a higher rate of flares than those who continued their stable dose. This has widely been interpreted as evidence for a flare-preventing efficacy. However, it must be recognized that this is not entirely certain. There are pharmacological mechanisms whereby the withdrawal of a drug may trigger adverse events independently of efficacy for preventing the same events, for example through the upregulation of receptors following withdrawal. The fact that in the above-mentioned trial the excess flares all seemed to occur during the first 6 weeks following withdrawal makes is hard to completely rule out such a mechanism. Other beneficial effects attributed to HCQ and antimalarials are generally not supported by randomized data. In recent years, a number of observational studies suggested a range of benefits for antimalarials, including decreases in long-term morbidities and even a survival benefit. These reports have led some SLE experts to recommend that antimalarials should be used for all patients with SLE unless contraindications exist. The recommended dosage for HCQ is 6.5 mg/kg/day in a single dose. Chloroquine and especially HCQ are considered very safe medications. Minor gastrointestinal intolerance and skin reactions occur infrequently. At high dosages antimalarials are associated with a risk for irreversible retinopathy (a 'bull's eye' lesion in the retina) but at the recommended dosages for lupus the risk is very small. Corneal deposits of the antimalarial can cause some visual symptoms such as halos around lights, and these may aggravate the fear of retinopathy. Periodic ophthalmological examinations are recommended.

Conventional Immunosuppressives

Agents such as azathioprine, methotrexate and cyclosporine A have been used for several decades in the management of SLE, but the evidence for their efficacy in nonrenal lupus has remained limited. The total weight of the available evidence nonetheless suggests that these medications can be useful in individual patients to accomplish the dual goal of optimizing control of the inflammatory manifestations of the disease while allowing the reduction of glucocorticoids. Because of its prominent role in the treatment of rheumatoid arthritis and other arthritides, methotrexate is often considered first when the patient has dominant musculoskeletal manifestations of SLE, and certainly when the patient has the not infrequent combination of features from both diseases, sometimes referred to as 'rhupus'. Methotrexate may also be considered in patients with recurrent or refractory serositis. Dosing of methotrexate is similar to that in rheumatoid arthritis, with a targeted weekly dose of 20–30 mg, and with folic acid supplementation added to lessen the risk for side effects. Gastrointestinal intolerance, mucositis, and (increased) hair loss are the main symptomatic side effects, and because of the risk for hepato- and myelotoxicity, monitoring of blood counts and liver enzymes is mandatory. Azathioprine is used across the entire range of lupus manifestations. It is usually dosed at 100–150 mg daily (or 1.5–2 mg/kg) initially whereas maintenance with lower doses is also possible. Side effects are similar to MTX and monitoring blood counts and liver function enzymes is also necessary with this medication. Cyclosporin A is used less frequently but may also be considered in a range of lupus manifestations. The starting dose is usually 2.5 mg/kg/day in two divided doses. The recommended maximum dose in autoimmune diseases is 5 mg/kg/day but in my experience not many SLE patients are able to tolerate this. The main safety considerations with this drug are hypertension and worsening renal function. Over the past decade mycophenolate mofetil (MMF) has become one of the most studied drugs for lupus, but mostly in the context of renal disease. For nonrenal disease manifestation much fewer data are available, but it seems reasonable to consider MMF also for the long-term management of moderate to severe and/or refractory disease. The usual doses are as given below for nephritis, and monitoring is similar to that for azathioprine. MMF has similar side effects as MTX and azathioprine, and may also cause adverse neuropsychiatric reactions.

Biologics

The biologic belimumab was approved for the treatment of patients with 'active SLE despite conventional therapy',[4,5] but clinicians may have had some difficulty in applying this approval to the concrete patient situation. In my opinion the most logical use for this agent, which has demonstrated efficacy but seems to have a rather slow onset of action, would be in the long-term management of patients with persistently active, recurrent and/or refractory disease. It does not make too much sense to base the decision whether to treat with belimumab or not on a momentary measurement of the SLE disease activity index or some other disease activity measure, despite the way the approval is worded. Rather, the clinician might consider the overall course of the disease in the individual patient, the degree of activity over the entire time that the patient has had the disease as well as recently, the frequency of flares, the amounts of glucocorticoids needed to control the disease, and the success (or rather, the lack thereof) in controlling disease with conventional agents. Belimumab is approved for use as a 4-weekly infusion at 10 mg/kg. Some trials also investigated 1 and 4 mg/kg but with mixed results,[9] and there is no information on other dosing intervals. A subcutaneous formulation is currently undergoing Phase III testing. Belimumab has generally been well-tolerated.[10] Infusion reactions have been uncommon. Some specific issues raised in connection with the approval of belimumab have not been fully resolved. Thus, the Phase III trials suggested that African–American patients with SLE had less benefit from the treatment than others, but several analyses based on prior studies and on observational data do not show such a difference. The clinical trials with belimumab excluded patients with severe renal or neuropsychiatric disease; currently a trial in lupus nephritis is ongoing.

Other Agents for the Long-term Management of Nonrenal Lupus

Over the decades, many other treatments have been proposed for the long-term management of patients with SLE. Dehydroepiandrosterone (DHEA; prasterone), a weakly androgenic adrenal steroid, was studied in two randomized trials at doses of 100–200 mg daily.[11,12] Both these trials fell short of achieving the primary outcome, but not by much, and most secondary outcomes supported some measure of efficacy. Since the results were 'negative' from a regulatory point of view no further studies of DHEA have since been done. It appears, however, that this hormonal agent may have some benefits for selected patients, particularly in controlling generalized symptoms and reducing the need for glucocorticoids. Side effects at the doses given above are not negligible and there is of course always a reasonable concern with long-term use of hormonal agents. Lower dosages of DHEA such as the ones used as adjunct treatment of adrenal insufficiency, 25–50 mg daily, have generally been found to be less effective in SLE.[13] The semisynthetic androgen danazole has occasionally been used in the treatment of hematological lupus manifestations.[14]

Thalidomide was originally developed as a hypnotic/sedative and subsequently found to cause a devastating teratogenicity in pregnant women. Case reports and case series have suggested efficacy in patients with cutaneous lupus.[15,16] In addition to the major concern regarding pregnancies, thalidomide is also associated with sedation and the risk for polyneuropathy.

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