Systemic Lupus Erythematosus: Which Drugs and When?

Ronald F van Vollenhoven

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

Short-term Treatment of Active Nonrenal SLE

For the patient who presents with a new diagnosis of SLE, or for the one who has a flare in previously established disease, the immediate need is to achieve control of the inflammatory process. In milder cases this can be accomplished by relatively simple means: a limited cutaneous rash may be amenable to treatment with topical glucocorticoids, and mild to moderate arthritis or pleurisy can often be treated with NSAIDs. As regards the latter it needs to be recognized that patients with SLE often seem poorly tolerant of these agents and that ibuprofen, the most commonly used NSAID, has been associated with aseptic meningitis as a rare but severe side effect for which patients with SLE appear to be at increased risk.

However, for the vast majority of lupus flares the initial treatment has to be systemic glucocorticoids. For most manifestations, prednisone at 0.25–0.5 mg/kg body weight (or equivalent) is sufficient to obtain good disease control within a few days to weeks. Following this, a taper of the glucocorticoids is initiated. Exactly how long to continue the original dose and how to taper, is highly variable in practice, in part due to large differences between the disease manifestations seen in individual patients, but also due to rather large differences in practice settings and therapeutic traditions. Efforts to standardize the manner in which to taper glucocorticoids have remained largely unsuccessful, and the proper use of glucocorticoids may well be considered a good example of the 'art' of medicine.

Glucocorticoids are associated with numerous risks and side effects. With short-term high-dose treatment, mood changes, increased appetite, fluid retention, changes in glucose metabolism, elevated blood pressure, and other metabolic changes are immediate and predictable side effects, while avascular necrosis and psychosis are uncommon and idiosyncratic but serious reactions. With longer-term treatment, other side effects of glucocorticoids become very common, including changes in body fat distribution (truncal obesity, 'moon face' and 'buffalo hump'), osteopenia and osteoporosis, skin atrophy, cataracts and dyslipidemias.

For patients with SLE manifestations in the CNS or peripheral nervous system, lungs, heart, GI tract or the eyes, the first line of treatment should be (much) higher dosages of glucocorticoids. When oral therapy is still considered appropriate 1 or even 2 mg/kg prednisone (or equivalent) should be given. In the initial phase it is advisable to divide the dosage over the day to achieve suppression of inflammation around the clock. This is not well tolerated by most patients, however, with insomnia becoming a major concern, and as soon as a measure of inflammation control is achieved the dosage can be consolidated to a single morning dose. For the most severely ill patients with critical SLE in the above-mentioned organ systems glucocorticoids should be given intravenously. A therapy tradition has existed for decades to administer methyl-prednisolone 1000-mg intravenously daily for 3 consecutive days (followed by high-dose oral treatment). The rationale for this exact dosage is not entirely clear. It has been shown that the very high serum levels of methyl prednisolone that are achieved may be consistent with the so-called 'nongenomic' effects of glucocorticoids mediated through cytoplasmic glucocorticoid receptors.^[3] Whether this is clinically relevant remains unproven.

For very severe manifestations with a life-threatening or organ-threatening potential some additional therapeutic options may be considered. The immediate addition to glucocorticoids of various immunosuppressives, including azathioprine, methotrexate, and cyclosporine A, may be advocated but it must be recognized that most traditional immunosuppressives work over rather long time courses and may not contribute much to the short-term therapeutic results. These medications will be discussed below under the 'Long-term treatment of nonrenal SLE: maintenance therapy' section. Cyclophosphamide, arguably the most effective of the conventional immunosuppressives used for SLE, may have a rapid effect in some patients that is not well-understood and has not been studied in detail. In this difficult clinical situation, many experts will give a single intravenous bolus dose of 750–1500 mg while at the same time treating with glucocorticoids as indicated above.

Other interventions that are used by experts when managing patients with severe or critical manifestations of SLE are intravenous immunoglobulin, plasmapheresis, and several other apheresis procedures. Evidence supporting the use of these comes from reported cases or case series and a good understanding of the mechanisms is still lacking. Nonetheless, in a few specific situations these agents may be considered more strongly: when there is evidence for antibody-mediated destruction of red blood cells and/or platelets intravenous immunoglobulin tends to be very efficacious; and when the patient with severe SLE also has evidence for microangiopathy (i.e., the clinical manifestations overlap with thrombotic thrombocytopenic purpura or hemolytic uremic syndrome) then plasmapheresis (or perhaps more properly, plasma exchange) may be considered more strongly evidence-based. Plasmapheresis can also be considered in lupus nephritis with coexisting anti-glomerular basement membrane antibodies.

Biologics in Acute SLE

The only approved biologic for SLE is belimumab, an antagonist of BLyS. The two successful clinical trials with belimumab were not designed to analyze the short-term efficacy but rather focused on long-term effects when given on top of existing standard therapy.^[4,5] The trial results revealed that disease activity (as measured by a modification of the SLE disease activity index) decreased rapidly upon entering the trial, but this applied both to patient groups who did and those who did not receive belimumab. The difference between the two groups only became manifest after 4–6 months of treatment, and this has been interpreted as showing that belimumab has a very slow onset of action. Later analyses showed that responses to belimumab were much more robust in patients who were positive for anti-DNA antibodies and who had low complement at baseline, and in these patients the differences between active treatment and placebo already became manifest after 8 weeks.^[6] Nonetheless, even when considering the latter findings, belimumab does not seem to have a role in the treatment of new SLE activity or a lupus flare. Rituximab (RTX) has not been approved for SLE and two randomized controlled trials with this biologic did not demonstrate efficacy. It is paradoxical then that clinicians have been quite interested in the possibility of using RTX in patients with severe or critical SLE. On account of the variability of such situations, the multiple therapies that are often employed simultaneously, and with the obvious risk of reporting bias, it is impossible to know at this time whether such efficacy could indeed be present.

The short-term treatment of active nonrenal SLE is summarized in Table 2.

1 2 3 4 5 6 7 8

Next Section

Abstract and Introduction
Short-term Treatment of Active Nonrenal SLE
Long-term Treatment of Nonrenal SLE: Maintenance Therapy
Treatment of Lupus Nephritis
Other Therapeutics Used in the Overall Management of SLE
Therapeutic Strategy: Treat to Target?
Conclusion
Future Perspective
References
Sidebar

Table 1. Objectives in the treatment of systemic lupus erythematosus, implications for the clinicians and main therapeutic options.
Therapeutic objective	Key implication for clinicians	Main therapeutic options	Other possible options
Symptom control	Use of rapidly acting agents tailored to the nature and severity of the manifestation	Glucocorticoids: topical for mild cutaneous lupus; low-dose oral for mild disease; moderate to high-dose oral for more severe disease; intravenous for very severe or life-threatening disease	Cyclophosphamide in severe disease; intravenous globulin, plasma exchange, rituximab in life-threatening situations but based on limited evidence
Prevent damage	Minimize both damage due to systemic lupus erythematosus and as consequence of medications, particularly glucocorticoids	Using antimalarials and immunosuppressives both to control disease in the long term and avoid 'spare' glucocorticoids	Belimumab Glucocorticoid-free induction therapy with rituximab?
Limit long-term morbidity and mortality	In addition to the above, attention to specific comorbidities such as cardiovascular disease	In addition to the above, proper attention to management of risk factors for cardiovascular disease and renal progression among others	–

Table 2. Summary of the short-term treatment of active nonrenal systemic lupus erythematosus.
Manifestation	First-line therapy	Additional therapies to consider
Mild cutaneous	Topical glucocorticoids	–
Minor arthritis, mild pleurisy	NSAIDs	Addition of antimalarials for long-term management
Most moderate SLE manifestations	Oral glucocorticoids 0.25–0.5 mg/kg prednisone (or equivalent)	Addition of antimalarials and/or immunosuppressives for long-term management
More severe organ-threatening SLE manifestations	Oral glucocorticoids 1–2 mg/kg prednisone (or equivalent)	Addition of antimalarials and/or immunosuppressives for long-term management
Very severe, organ-threatening or life-threatening SLE	Intravenous 'pulse' glucocorticoids: methylprednisolone 1000 mg daily × 3 days followed by high-dose oral glucocorticoids	Addition of intravenous 'bolus' cyclophosphamide; use of intravenous γ-globulin; plasma exchange; rituximab?

SLE: Systemic lupus erythematosus.

Table 3. Summary of the long-term treatment of nonrenal systemic lupus erythematosus.
Manifestation	Mainstay of therapy
Persistent but mild arthritis and pleurisy among others	NSAIDs and antimalarials
Persistent or frequently recurring moderate-to-severe systemic lupus erythematosus manifestations	Antimalarials and/or immunosuppressives; belimumab
Long-term inability to control disease without glucocorticoids	Antimalarials and/or immunosuppressives; belimumab

Table 4. Treatment of severe (WHO class III–V) lupus nephritis.
	First-line treatment	Alternative	Selected new options currently in clinical trials
Induction	High-dose glucorticoids plus: lower-dose cyclophosphamide ('Euro-Lupus' 500 mg biweekly × 6) or mycophenolate mofetyl	High-dose glucorticoids plus: higher-dose cyclophosphamide ('NIH' 1000–1500 mg monthly × 6) – for very severe disease	Rituximab for refractory disease; belimumab for lupus nephritis; and rituximab as first-line therapy without oral glucocorticoids
Maintenance	Mycophenolate mofetil	Azathioprine	Belimumab

Sidebar

Executive Summary

Treatment of systemic lupus erythematosus needs to fulfill a number of objectives

Symptoms of systemic lupus erythematosus (SLE) must be brought under control to avert immediate consequences and afford the patient a better quality of life.
Damage resulting from the disease and its treatment must be minimized.
Long-term morbidity and mortality must be avoided.

Short-term treatment of active nonrenal SLE

The immediate need is to achieve control of the inflammatory process.
For the vast majority of lupus flares the initial treatment has to be systemic glucocorticoids.
For most manifestations, prednisone at 0.25–0.5 mg/kg body weight (or equivalent) is sufficient to obtain good disease control.

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. Therefore, many clinicians will start longer-term, maintenance therapy when the patient is being treated for a disease flare or shortly thereafter.
Drugs most commonly used in this setting are antimalarials and conventional immunosuppressives.

Treatment of lupus nephritis

Treatment can be divided into an initial phase where treatment is most intense and aimed at controlling disease activity by suppressing autoimmune inflammation, and a maintenance phase with less intensive treatment in order to maintain control of the disease, prevent flares and reduce long-term damage.

Other therapeutics used in the overall management of SLE

Patients frequently suffer from symptoms the relation of which to active autoimmune inflammation has remained hard to determine, such as fatigue, lassitude, arthralgias, myalgias, headaches and mild cognitive symptoms.
These symptoms often do not respond to conventional immunosuppressives, and other therapeutics can be employed that may have effects for such symptoms.

Therapeutic strategy: treat to target?

SLE may not be amenable to a single therapeutic target, but several targets may have to be considered simultaneously, including remission, absence of flares, prevention of damage and minimization of glucocorticoids.

Conclusion

Through judicious use of the available medications good therapeutic results and a reasonable long-term prognosis can be achieved for the majority of patients.