Abstract
The improving prognosis in patients with systemic lupus erythematosus is due in no small part to refinements in treatment. One idea is to tailor the treatment to the specific clinical features. For example, the treatment of cutaneous lupus may require antimalarial and topical agents initially, with more severe cases requiring dapsone or even thalidomide. Conversely, renal involvement in systemic lupus erythematosus is better treated with corticosteroids and immunosuppressive agents such as intravenous cyclophosphamide, mycophenolate mofetil or azathioprine. It is very clear that comorbidities such as steroid-induced diabetes mellitus, hypertension and osteonecrosis have been responsible for a great deal of the morbidity associated with systemic lupus erythematosus and must be aggressively managed. In addition to ‘traditional’ agents, newer medications such as rituximab, abatacept and B-lymphocyte stimulator antagonists are showing great promise and will probably be an an important part of the management of severe lupus in the future.
Keywords
The prognosis of systemic lupus erythematosus (SLE) has improved remarkably since the early 1950s. There are many reasons for this, the first being the development of new serological tests resulting in earlier diagnosis and treatment, before permanent sequelae of the disease develop (such as renal failure). Second, with the availability of such laboratory testing and with increased awareness, patients with milder disease who may have been previously overlooked, are being diagnosed. Third, and most importantly, numerous advances in the treatment of SLE have been introduced over the years, beginning with the introduction of antimalarials and corticosteroids in the early 1950s, the popularization of cytotoxic agents in the 1970s and 1980s, and biological agents in the past few years. Finally, comorbidities that importantly influence outcome in SLE, such diabetes mellitus, accelerated cardiovascular disease and depression, are being better managed with medications and patient education. As with any other chronic disease, the choice of treatment should achieve a favorable balance between the benefits and adverse effects of therapy.
There are two broad categories of SLE manifestations with respect to therapy. Mild-to-moderate disease includes mucocutaneous and musculoskeletal manifestations (e.g., arthralgias, arthritis and myalgias), serositis (e.g., pleurisy, pericarditis and peritonitis) and constitutional symptoms (fatigue). In general, this group of patients should be treated conservatively; although, not uncommonly, low-to-moderate doses of steroids are required. More aggressive approaches are reserved for cases in which there is a high risk of major organ damage (e.g., renal, pulmonary or CNS) and death.
Beyond the specific lupus manifestations, there are several health issues that need to be assessed in these patients: adequate control of hypertension, diabetes and hyperlipidemia; prevention of steroid-induced osteoporosis; management of specific pathologies, for example, prophylaxis and treatment of thrombosis associated with antiphospholipid antibodies; and prevention and control of infections related to immunosuppression. This article will summarize the current status of lupus treatment, highlighting new developments with promise for the future.
Treatment of mild-to-moderate disease
Many patients with SLE in fact do not have severe disease, and one of the big improvements in the management of this disease over the past few decades has been the refinement of standard medications (such as corticosteroids), where a policy of using the lowest dose necessary for the shortest time required has led to lesser toxicity. Certain manifestations of SLE are managed quite differently from aggressive disease.
Mucocutaneous manifestations
Photosensitivity
Many, if not most, SLE patients develop erythematous rashes on sun exposure. It is well known that both ultraviolet (UV)B (290–320 nm) and UVA (320–400 nm) rays can provoke lupus flares in photosensitive individuals. In fact, it has recently been shown that UV light-induced injury induces apoptosis, necrosis and cytokine production [2]. Therefore, avoidance of sun exposure is an important part of SLE treatment. Different measures include the use of a sunscreen with sun protection factor of greater than 15, para-aminobenzoic acid (PABA)-free for individuals with sensitive skin. Ideally, sunscreen should be broad in its UV spectrum and water resistant [3]. In addition, the wearing of long sleeves and broad-brimmed hats when venturing out into the sunlight is recommended.
Other cutaneous manifestations
In most patients, the cutaneous manifestations of the disease (especially photosensitive and malar rashes, alopecia and oral ulcers) occur mainly during disease flares, and improve with systemic treatment. However, certain types of SLE-associated rashes, including subacute cutaneous lupus erythematosus (LE) or discoid LE may worsen without evidence of systemic disease activity [4]. The treatment of the patient with lupus and cutaneous manifestations should involve both the rheumatologist and dermatologist.
Oral lesions
Oral and nasal ulcers are painless in most SLE patients, coincide with disease flares and heal without sequelae once the flare is resolved. For those with symptomatic oral lesions, topical corticosteroids (e.g., 0.05% fluocinonide gel, 0.05% clobetasol gel, dexamethasone elixir and triamcinolone acetonide) and antimycotic agents (e.g., clotrimazole troches, nystatin suspension and chlorhexidine rinse) should be considered. Intralesional corticosteroids are rarely utilized for symptomatic relief in more refractory patients, although these are best administered by a dentist or oral surgeon [8]. In the rare patient where the oral ulcers are the dominant complaint (and infectious causes have been ruled out) and who has not responded to the above measures, systemic immunosuppressive agents could be considered, including corticosteroids or azathioprine, methotrexate and mycophenolate mofetil.
Treatment
The most common medications used for cutaneous lupus manifestations are as follows (see Figure 1).
Treatment of mucocutaneous manifestations.
Topical glucocorticoids
These medications should be prescribed using the least potent preparations necessary and the lowest effective dose. Low-to-medium potency nonfluorinated preparations (such as hydrocortisone) are recommended for lesions involving the face. For the trunk and extremities, medium-potency fluorinated corticosteroids (e.g., betamethasone valerate or triamcinolone acetonide) can be chosen; high-potency preparations (e.g., betamethasone dipropionate or clobetasol) are reserved for hypertrophic lesions, and for lesions on palms and soles. The use of high-potency glucocorticoids should be limited, if possible, to 2 weeks, after which time less potent preparations should be used for a short period of time. In order to minimize the risk of skin atrophy and telangiectasia, fluorinated steroid preparations should be avoided on the face and intertriginous areas. Occlusive agents, such as plastic wrap or tape, may be helpful to potentiate the steroid effect. In treatment-resistant areas, steroids injected intralesionally may be necessary.
Antimalarials
Antimalarial drugs are thought to exert their therapeutic effect by interfering with antigen processing in macrophages and other antigen-presenting cells by increasing the pH inside the lysosomal vacuoles. They are deposited in the skin, where they absorb UV light. They also inhibit prostaglandins, cytokine production and neutrophil migration, and block superoxide release. There are several antimalarials available: chloroquine, although still used extensively outside the USA, is not used as often now due to its retinal toxicity. Hydroxychloroquine is the most common antimalarial agent currently utilized by SLE patients. It is generally well tolerated at the low dose used in SLE (200 mg twice daily). Quinacrine has been used alone, but is more efficacious when used in combination with either hydroxychloroquine or chloroquine in both cutaneous and musculoskeletal involvement in SLE.
The most common toxicities of antimalarials are gastrointestinal, including nausea, bloating and diarrhea. Less commonly observed are dizziness, skin rashes and hyperpigmentation. Ocular toxicity is a very uncommon complication, found more frequently with chloroquine than with hydroxychloroquine. There are two forms of antimalarial-associated ocular involvement: deposits in the cornea that can be associated with photophobia, visual halos and blurred vision (it frequently resolves with dose reduction); and the rare occurrence of true retinal toxicity, which is associated with loss of night vision and scotomata. It occurs with doses of hydroxychloroquine of greater than 6 mg/kg/day, or with cumulative doses of greater than 800 g, and is most likely to occur in older patients. Most rheumatologists and ophthalmologists recommend periodic (annual at least) ophthalmological examinations to identify retinal toxicity early. Other complications of antimalarial use are neuropathy, myopathy, depigmentation and hyperpigmentation of the skin. Quinacrine use has been associated with pigment changes (yellow/orange discoloration of the skin), aplastic anemia (rarely) and neuropsychiatric complications, and extremely rarely with ocular toxicity.
For a patient with severe cutaneous LE who is intolerant or resistant to topical glucocorticoids and antimalarials, dapsone is generally tried next and is effective in discoid lupus, urticarial vasculitis, bullous lupus and oral ulceration. The recommended dose is 25–200 mg/day. Hemolysis is a common complication, usually dose-related, and in certain sensitive individuals, such as those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, may require discontinuation of the drug. Less commonly seen are methemo-globinemia, sulfhemoglobinemia and exfoliative dermatitis. Other agents include the infamous thalidomide, which several studies have shown to be effective in severe cutaneous lupus, especially in patients who have been resistant to other therapies [6]. Other than its most notorious complication in pregnant patients of fetal malformations such as phocomelia, other side effects related to thalidomide use are drowsiness, abdominal pain and peripheral neuropathy. Methotrexate, a folic acid antagonist, has been used at low doses (7.5–25 mg once weekly) in patients with recalcitrant cutaneous lupus (chronic discoid lupus and subacute cutaneous lupus) that is resistant to other treatments [34]. The most common complications associated with methotrexate use are oral ulcers, gastrointestinal symptoms and hepatotoxicity. Side effects may be decreased with the addition of folic acid (1 mg/day). Hepatic transaminases and serum urea nitrogen and creatinine should be monitored regularly. At this point, serial liver biopsies for diagnosing liver toxicity are not routinely required. Tacrolimus is a T-cell inhibitor and can be used topically in patients with cutaneous lupus. Retinoids (e.g., isotretinoin, etretinate and topical tretinoin) are also utilized in the treatment of severe cutaneous LE, especially in patients with hypertrophic lesions, although their effect is frequently only temporary and their discontinuation is often followed by a flare. Systemic retinoid use can also be associated with cheilitis, teratogenesis and hyperlipidemia. Clofazimine seems to have anti-inflammatory, immunosuppressive and antimicrobial properties, and was shown in one study to be as effective as chloroquine in controlling cutaneous lupus lesions [7]. Side effects are usually mild and may include gastrointestinal symptoms, skin dryness, and skin and conjunctival reddish-brown pigmentation. More serious side effects include enteropathy and splenic infarction with doses higher than 100 mg/day used for prolonged periods of time. Laser treatment can be effective for telangiectasia and discoid lupus lesions.
Musculoskeletal manifestations
Myalgias, arthralgias and arthritis are very common in patients with SLE. In general, treatment of musculoskeletal complaints can begin with nonsteroidal anti-inflammatory drugs (NSAIDs). Gastrointestinal complications such as bleeding and peptic ulcer disease are seen less often with selective cyclooxygenase (COX)-2 inhibitors; however, potential detrimental cardiovascular side effects may limit their use. In order to prevent peptic ulcer disease when using nonselective NSAIDs, the addition of proton pump inhibitors may be necessary, especially in symptomatic patients. Special caution should be utilized for SLE patients with renal disease, in whom potential renal complications of NSAIDs (e.g., interstitial nephritis, and transient fall in glomerular filtration rate) can be especially problematic. In addition, hepatotoxicity and, less often, CNS complications such as dizziness, confusion and, rarely, aseptic meningitis can occasionally be seen in patients receiving NSAIDs. Other non-narcotic analgesics such as acetaminophen or tramadol may be preferable.
For those patients in whom NSAIDs are not effective in controlling pain and inflammation or are contraindicated, hydroxychloroquine (200 mg twice daily), or low doses of glucocorticoids (prednisone 5–10 mg/day) should be considered. It is important to emphasize the adverse effects associated with prolonged use of systemic glucocorticoids, including alterations of fat distribution, glucose intolerance, osteoporosis and cataracts, among others. A steroid-sparing agent, such as methotrexate in weekly doses of 10–20 mg, is recommended in some cases.
Dehydroepiandrosterone (DHEA) at doses of 100–200 mg/day has recently been shown to provide symptomatic relief to lupus patients with mild-to-moderate disease, including constitutional symptoms, myalgias and oral stomatitis [8]. The most common side effects include acne, hirsutism and reduction in serum high-density lipoprotein (HDL) cholesterol. Since SLE is associated with an increased frequency of cardiovascular disease, this is of concern. Further long-term studies are necessary to elucidate the impact of DHEA in patients with SLE.
Serositis
Serositis, including pleurisy, pericarditis and peritonitis, may respond to NSAIDs, antimalarials or low doses of systemic glucocorticoids. In resistant cases, high doses of steroids, intravenous immunoglobulins or cyclophosphamide can be used. Patients with large effusions causing mechanical effects (e.g., cardiac tamponade or respiratory failure) may require surgical procedures such as pleurodesis or pericardial fenestration.
Fatigue
‘Lupus fatigue’ is a distressing and extremely common complaint in patients with SLE, may occur independently of disease activity and is refractory to most treatment measures. In some patients, this may be a reflection of fibromyalgia (which in most series occurs in less that 10% of SLE patients and should be ascertained by careful clinical evaluation). Although not studied in any controlled manner, it has been a long-held opinion that adequate rest is important during periods of active disease. With the weight gain, muscular and cardiac deconditioning and osteoporosis that can accompany either disease flares or the treatment thereof, is important to recommend a regular exercise program. Depression and sleep deprivation can contribute to systemic complaints and therefore need special attention. DHEA may be effective in some patients with refractory symptoms. Hydroxychloroquine can also be used, although its efficacy in improving fatigue is questionable.
Treatment of moderate-to-severe manifestations of SLE
When SLE presents with rapidly progressive multiorgan failure, institution of aggressive therapy is necessary to reduce morbidity and save lives. SLE may cause life-threatening renal, cardiac, pulmonary, hematological or neurological complications.
Lupus nephritis
Renal failure was the leading cause of death in the predialysis era. It still is a leading cause of morbidity in this disease. Renal involvement, according to the current American College of Rheumatology (ACR) classification criteria, is defined as persistent proteinuria greater than 0.5 g/day a score greater than 3 on dipstick or the presence of cellular casts. Renal biopsy is frequently utilized early in the disease course. The WHO classification includes use of light microscopy, immunofluorescence and electron microscopy findings. In the most recent 2003 classification (International Society of Nephrology/Renal Pathology Society) [35], lupus nephritis is classified into six categories:
Class I: minimal mesangial changes
Class II: mesangial proliferative alterations
Class III: focal glomerulonephritis (GN)
Class IV: diffuse GN
Class V: membranous lupus nephritis
Class VI: advanced sclerosing lupus nephritis
However, lupus nephritis is a dynamic process with some cases evolving from one pathological category to another. When there is worsening of proteinuria or a rise in the serum creatinine, it may be necessary to perform a repeat biopsy on the patient. In general, patients with lesions limited to the renal mesangium have a better prognosis, while those with proliferative lesions fare less well. Patients with diffuse proliferative GN (Class IV) have the least favorable prognosis. Prognostic factors for a poor outcome in lupus nephritis include clinical factors such as non-Caucasian ethnicity, hypertension, pregnancy, severe extrarenal activity; laboratory parameters such as thrombocytopenia, the presence of severe nephrotic syndrome and azotemia at presentation; and biopsy parameters such as Class IV GN, the presence of cellular crescents or fibrinoid necrosis, having a high activity or chronicity index, and the presence of subendothelial deposits. This underscores the importance of the renal biopsy not only in prognosis but also in planning treatment. A patient with a high activity and a low chronicity index would mandate aggressive immunosuppression, whereas a patient with a low activity and a high chronicity score would probably be managed more conservatively, as the renal damage is likely to be irreversible. Associated cardiovascular risk factors should be taken in consideration, leading to lifestyle changes and pharmacological treatments. In general, immunosuppressive therapy is required in patients with Class IV GN and in those with refractory Class III disease, including glucocorticoids in combination with any of the following: cyclophosphamide; azathioprine; mycophenolate; or, less commonly, cyclosporine, fludarabine and cladribine, among others [30].
First, it needs to be emphasized that renal disease and even renal failure can occur as a complication of nonrenal causes. Severe hypertension occurs not uncommonly, and hypertensive nephrosclerosis can result in renal failure, mandating a need for blood-pressure control in SLE patients. Antiphospholipid antibody syndrome can cause renal vein thrombosis or a thrombotic microangiopathy. Drug-induced nephropathy can also occur, complicating underlying SLE-related renal pathology or even occurring spontaneously. NSAIDs can reduce renal blood flow and the glomerular filtration rate. Other agents such as antibiotics or pamidronate can cause tubular toxicity. A summary of the treatment of lupus nephritis is shown in Table 1.
Treatment of lupus nephritis.
Treatment Cyclophosphamide
Cyclophosphamide is an alkylating agent that can be either administered orally or intravenously, and is ultimately metabolized in the liver to phosphoramine mustard. The lower toxicity by the intravenous route has made this the preferred method of administration. Traditionally, cyclophosphamide has been used for prolonged periods of time, starting with a monthly ‘induction’ regimen for 6 months (0.5–1.0 g/m2 of body-surface area), followed by quarterly administration for another 12–24 months. The side effects of cyclophosphamide include nausea and vomiting, usually presenting 12–24 h after administration of the intravenous pulse, making pretreatment with antiemetics advisable. Alopecia is also seen frequently and is reversible. Cytopenias, with the peripheral blood white blood cell (WBC) count reaching its nadir 8–12 days after administration. If the total WBC count falls below 2000/mm, the next dose should be decreased or held.
Malignancies are a potential complication of cyclophosphamide administration, particularly lymphoreticular neoplasms, leukemias and transitional-cell carcinoma of the bladder, although one recent study of 7312 SLE patients from 20 centers across four continents found no increased risk in drugs used in the treatment of SLE and malignancy [40]. Hemorrhagic cystitis, less commonly observed with the intravenous pulse and more frequent with oral administration, seems to be related to chronic exposure of the bladder epithelium to the toxic metabolite acrolein. This complication can be prevented by treatment with mesna, given at 20% of the total dose of cyclophosphamide, starting immediately before administration of the drug and every 3 h thereafter for a total of four doses.
Pregnancy should be avoided while taking cyclophosphamide, due to its high teratogenic potential. Since SLE is a disease affecting primarily women of childbearing age, the high incidence of ovarian failure associated with cyclophosphamide use is unfortunate. Recent publications have revealed that treatment with gonadotropin-releasing hormone analog (GnRH-a) during cyclophosphamide therapy may be associated with a significant reduction of premature ovarian failure in these women [12].
Although the induction of treatment of nephritis has classically been with a 6-month course of intravenous cyclophosphamide, maintenance treatment thereafter now includes either mycophenolate mofetil or azathioprine, which have fewer side effects than prolonged used of cyclophosphamide (see below) [10,12,16,41,42]. Furthermore, it has been shown by one group that low-dose regimens of intravenous cyclophosphamide (six fortnightly intravenous pulses at a fixed dose of 500 mg, with a cumulative dose of 3 g) are as effective as higher-dose intravenous regimens (0.5 g/m2 of body surface area, 6-monthly pulses followed by two quarterly pulses) [43].
Azathioprine
Azathioprine is an imidazolyl derivative of mercaptopurine. It antagonizes purine metabolism and may inhibit synthesis of DNA, RNA and proteins. This drug is most commonly used for maintenance therapy in lupus nephritis or as a steroid-sparing agent. Azathioprine is administrated orally at doses of 1–3 mg/kg/day. Among its side effects are alopecia, skin rashes, gastrointestinal effects (nausea, vomiting and diarrhea), bone marrow suppression, hepatotoxicity and retinopathy.
Mycophenolate mofetil
Mycophenolate mofetil is a relatively new immunosuppressive drug, approved for use in organ transplantation, which inhibits purine synthesis, lymphocyte proliferation, T-cell dependent antibody responses and the expression of lymphocyte surface-adhesion molecules. It is usually administered at lower doses than those used for preventing transplant rejection. Recent studies have shown it to be effective and well tolerated at oral doses of 500–3000 mg/day [11]. Recent data suggest that mycophenolate mofetil may serve as an alternative to intravenous pulse cyclophosphamide in both the induction and maintenance treatment of lupus nephritis [33].
The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections (e.g., cytomegalovirus and herpes).
Other agents
These include cyclosporin A, used in doses of 3–5 mg/kg, which has been shown to be effective in reducing disease activity and the degree of proteinuria in patients with lupus. The most limiting side effect is nephrotoxicity. Fludarabine and cladribine, which are purine nucleoside analogs with activity against dividing and resting lymphocytes, were shown to be effective in treating membranous nephropathy. They were also associated with myelosuppression with consequent infections. At this point, their use is largely investigational. Total lymphoid irradiation was introduced in the early 1980s for the treatment of severe SLE. In general, patients treated with total lymphoid irradiation did not appear to have better survival and lower incidence of end-stage renal disease, and there are no current indications for its use [13]. Plasmapheresis therapy has been abandoned for the treatment of lupus nephritis since in controlled studies it has not shown any benefit on outcome.
Experimental biological treatments
With the effectiveness of tumor necrosis factor (TNF)-α blockers in rheumatoid arthritis, biological treatments constitute a novel choice for the treatment of rheumatic diseases. For the treatment of lupus nephritis, several agents are under development, including rituximab, which is a mouse–human immunoglobulin (Ig)G1k chimeric anti-CD20 antibody initially approved for the treatment of low-grade B-cell non-Hodgkin's lymphoma, that works by selectively eliminating peripheral B cells [32]. It has now received FDA approval for the treatment of rheumatoid arthritis. In an open-label trial, rituximab was used to treat proliferative lupus nephritis in ten patients [15]. In eight of ten patients, partial remission was achieved within a median of 2 months. Complete remission later occurred in five patients, and was sustained in four patients at 12 months. A controlled trial is necessary to confirm these clinical results. Rituximab has also been effective in treating autoimmune hemolytic anemia and thrombocytopenia refractory to glucocorticoids. US FDA approval for the use of rituximab for SLE is still pending at the time this article was written. Anti-CD40 ligand monoclonal antibody (BG9588) was shown in one open-label, multiple-dose trial conducted in patients with proliferative lupus nephritis to reduce levels of anti-dsDNA antibodies, increase C3 concentration and decrease hematuria in patients with proliferative lupus nephritis, although the study was terminated prematurely due to thromboembolic complications. Some other studies have failed to demonstrate efficacy. Some other experimental treatments currently under investigation include abatacept, interleukin (IL)-10, B-lymphocyte stimulator antagonists and neutralizing antibodies against IL-10 and C5b.
Autologous hematopoietic stem-cell transplant
Based on previous findings, where remission of severe SLE after bone marrow transplant was achieved in patients receiving this treatment for concomitant leukemias and lymphomas, both allogenic and autologous hematopoietic stem-cell transplantion has been attempted in patients with severe refractory disease resistant to other treatments [18]. Most of the studies available in patients with lupus treated with bone marrow transplantation have selection bias, where only those patients with more severe and refractory disease received this modality of therapy; this makes difficult to interpret results. The significant morbidity and mortality associated with this treatment, its considerable expense and the high recurrence rate of the disease, make this choice an experimental approach that should be reserved for the most aggressive and refractory cases of lupus, and in centers that are both equipped to deal with and have significant experience in implementing this approach.
Renal transplant in patients with SLE
In patients with end-stage renal disease, the best option is kidney transplantation. Despite poor early graft results, the prognosis has been improving with the development of new immunosuppressive drugs. In a recent study by Moroni and colleagues, 33 patients with lupus nephritis received 35 kidney grafts, with long-term patient and graft survival probabilities similar in patients with SLE and matched controls [27]. There was a trend toward thrombosis, particularly in antiphospholipid antibody-positive patients. Nephritis recurred in less than 10% of patients with SLE and did not influence graft survival.
Neuropsychiatric lupus
Neuropsychiatric lupus involves a wide spectrum of CNS and peripheral nervous system manifestations, ranging from purely psychiatric disorders to quadraparesis and coma [14]. The treatment of neuropsychiatric lupus truly represents a challenge for the physician taking care of these patients, due to the lack of objective diagnostic and monitoring measures and the multifactorial etiology of neuropsychiatric disease in patients with SLE. CNS disease in a lupus patient can result not only from SLE itself, but also from comorbidities not directly associated with SLE activity, such as side effects of medications, infection or accelerated atherosclerosis. Some of these etiological factors include vascular injury of intracerebral vessels, autoantibodies against neural antigens, ribosome and phospholipid-associated proteins, and local generation of cytokines. A functional deficit, such as hemiparesis, could result from active SLE (vasculitis), thrombosis due to antiphospholipid antibodies, or from accelerated atherosclerosis due to secondary hyperlipidemia and hypertension resulting form SLE. Therefore, the first step is to discern whether the symptom in question is attributable to active lupus. Treatment remains empiric in the absence of controlled studies, and includes immunosuppression, focused symptomatic interventions, and the management of associated or contributing comorbidities [31]. For some severe manifestations felt to be due to active SLE, such as transverse myelitis and diffuse cerebritis, a high dose of glucocorticoids either intravenously or orally, should be administrated, for example, methylprednisolonone intravenous 1–2 g/day. For rapidly progressive or severe CNS involvement, intravenous cyclophosphamide may be given, although there are no controlled trials available. If the neuropsychiatric disease is due to thrombosis of intracranial vessels secondary to antiphospholipid antibodies, anticoagulation with either unfractionated heparin, low-molecular-weight heparin, warfarin or aspirin should be considered. Recently, the Antiphospholipid Antibodies and Stroke Study (APASS) data demonstrated that there was no difference in the risk of thrombotic events in patients treated with warfarin compared with aspirin-treated patients, with first ischemic stroke and a single positive antiphospholipid antibody test [46]. Therefore, patients who do not have another indication for anticoagulation and have a positive antiphospholipid test may be treated with either aspirin (325 mg/day) or moderate-intensity warfarin (international normalized ratio: 1.4–2.8). Additional adjuvant measures are necessary to control neuropsychiatric manifestations, including anticonvulsants for persistent seizures, antidepressants for mood disorders and antipsychotic drugs for psychosis. Migraine headaches may improve with glucocorticoids; however, in some cases the patient may also respond to antimigraine therapy. A multidisciplinary medical and paramedical approach in these cases, from affective disorders as well as physical and occupational therapy, is invaluable. A summary is shown in Box 1.
Treatment of neuropsychiatric lupus.
Glucocorticoids (oral or intravenous)
Cyclophosphamide/other immunosuppressive agents
Anticoagulation (if disease is secondary to thrombosis)
Supportive treatment (anticonvulsants, antipsychotics)
Cytopenias
Cytopenias, including Coombs-positive hemolytic anemia, thrombocytopenia and leukopenia, accompany SLE flares. In general, leukopenia does not require treatment. Coombs-positive hemolytic anemia and thrombocytopenia (especially when <50,000 mm3) are initially treated with glucocorticoids. A rise in the platelet count is expected to occur within 3–5 days. In more refractory patients, intravenous Ig (IVIG) can be used (10 mg/kg/day for 5–10 days) [22]. IVIG modulates the immune response by interacting with various Fcγ receptors, inhibiting complement and regulating the production of cytokines. The response to IVIG therapy is usually transient, requiring the administration of repeated infusions. Therefore, the short duration of its effect and its high cost limit its use to patients with thrombocytopenia or hemolytic anemia refractory to high doses of corticosteroids. It should be noted that there are numerous case reports of the effectiveness of IVIG for other manifestations of SLE (including renal, CNS and musculoskeletal involvement), but without any controlled studies to guide us, its high cost and the short supply of most IVIG preparations, it is difficult to recommend this treatment as a routine measure at this time, except as previously noted. Splenectomy is an option in patients not responding to other measures. Some patients require further use of cytotoxic agents to prevent relapses. There are some incidental reports that azathioprine, mycophenolate mofetil and cyclosporine may also be effective in this setting [36–38].
Treatment of SLE during pregnancy & lactation
The treatment of SLE during pregnancy can be challenging for different reasons. First, SLE itself or the medications used in the treatment thereof can adversely affect the fetus; and second, some complications of pregnancy may mimic SLE manifestations (e.g., livedo reticularis, malar rash, myalgias, arthralgias, fatigue, hypertension and proteinuria). High-activity lupus during pregnancy leads to complications including increased premature birth and a decrease in live births. Almost a quarter of these pregnancies may result in fetal loss. Women with a history of renal disease are at particularly high risk of developing highly active lupus during pregnancy. Therefore, it is very important to have the disease well controlled at least 6 months prior to conception if possible in order to prevent complications. It is important to prevent increases in lupus activity and, if a lupus flare begins to appear, treatment must be started quickly [44].
The choice of corticosteroids should be based on whether the mother or the fetus needs to be treated. If the goal is treating the mother, hydrocortisone, cortisone or prednisone should be chosen. Glucocorticoids that cross the placenta and therefore can be used for the fetus are dexamethasone and betametasone. Side effects include diabetes mellitus, hypertension, sodium retention, edema and premature rupture of membranes in the mother. Doses greater than 10 mg/day given during the first trimester have been related to an increased risk of cleft palate. Stress doses of hydrocortisone are recommended during labor and delivery. The use of glucocorticoids is not a contraindication for lactation [24], although some authors recommend breastfeeding after 4 h of the last corticosteroid dose if the patient is receiving doses of prednisone greater than 20 mg/day. NSAIDs have been associated with oligohydramnios, gestation prolongation, alteration of fetal urinary output, premature rupture of membranes, and increased risk of hemorrhage in the mother and the fetus. Therefore, it is desirable to discontinue NSAIDs 6–8 weeks prior to delivery. NSAIDs can be continued during lactation; however, there is a potential risk of jaundice and kernicterus in the newborn. Hydroxychloroquine crosses the placenta, although at the doses used in SLE, fetal toxicity has not been demonstrated. Some studies have suggested that it is probably safer to continue the drug throughout pregnancy to prevent flares than the potential fetal toxicity associated with its use [28]. Methotrexate, leflunomide and cyclophosphamide are highly toxic to the fetus and, as such, should be avoided during pregnancy. When SLE is active and life-threatening and does not respond to high doses of glucocorticoids, some alternatives that can be used with caution are azathioprine and cyclosporine. Mycophenolate mofetil has not been well studied in pregnancy. Some case reports suggest mycophenolate mofetil has teratogenic effects. Therefore, its use is not recommended during pregnancy and it should be discontinued at least 6 weeks prior to conception. Most of these cytotoxic agents are excreted in breast milk, therefore breastfeeding is not recommended if their use is required.
It has been known for over 20 years that antiphospholipid antibodies are recognized risk factors for pregnancy loss. The best treatment for women during pregnancy with antiphospholipid antibodies and one or more fetal losses after 10 weeks' gestation without previous episodes of thrombosis is controversial. Current recommendations propose that women with antiphospholipid antibodies and a history of two or more early pregnancy losses or one or more late pregnancy losses without prior history of thrombosis should receive treatment with combination aspirin and heparin (unfractionated or low-molecular-weight) during pregnancy. Low-dose aspirin (81 mg/day) should be initiated with attempted conception and, once a viable pregnancy is confirmed, heparin (5000–10,000 units every 12 h) or low-molecular-weight heparin in prophylactic doses should be given (enoxaparin 40–80 mg, dalteparin 5000 units or nadroparin 3800 units, administered once daily). Heparin and aspirin should be continued until late in the third trimester [45]. Coumadin use is contraindicated during pregnancy due to its potential teratogenicity. Table 2 summarizes the treatment of SLE during pregnancy and lactation.
Treatment of lupus during pregnancy and lactation.
FDA: Food and Drug Administration; NSAID: Nonsteroidal anti-inflammatory drug.
Diet & SLE
Patients with SLE frequently ask if there are changes in diet that can exacerbate or ameliorate SLE. In general, there are none (other than a well-balanced diet low in saturated fats and restricting caloric intake to minimize the inevitable weight gain associated with high-dose glucocorticoids). However, dietary supplementation with omega-3 fish oils has been shown to have a beneficial effect in both humans and mice with SLE [39]. However, the amount of fish oil required to have an effect is regarded by many patients as unpalatable, and thus the feasibility of this approach is questionable.
Conclusion
Treatment of SLE is challenging, requiring a multidisciplinary and individualistic approach. There are no curative treatments and most of the available treatments are associated with considerable side effects. Therefore, the medication-related adverse effects should always be weighed against the morbidity associated with the untreated disease. Several new medications and regimens have been introduced in the past few years for the treatment of different manifestations of SLE that may provide more effective and less toxic alternatives. With a number of biological agents that will be released in the near future, such as rituximab and abatacept, the promise for the future treatment of SLE looks excellent.
Future perspective
Recent innovations in the treatment of other rheumatic diseases such as rheumatoid arthritis and ankylosing spondylitis with biological agents such as TNF blockers have dramatically changed the management of these diseases, and portend dramatic changes in the management of SLE. Although significant improvement over the sole use of high-dose corticosteroids has been afforded with the addition of immunosuppressive agents such as cyclophosphamide, mycophenolate and azathioprine to the management of SLE, biological therapies such as rituximab are being tested, and new agents are arriving yearly. Within 10–15 years it is entirely plausible that nonspecific anti-inflammatory and immunosuppressive agents such as corticosteroids and cyclophosphamide may be replaced by biological agents targeted against specific immunological targets involved in SLE activity.
Executive summary
Many patients with systemic lupus erythematosus (SLE) do not in fact have severe disease, and do not require treatments associated with serious side effects (i.e., high-dose glucocorticoids or immunosuppressive agents).
Cutaneous lupus is best managed by avoidance of sun exposure (including the use of sunscreens), followed by antimalarials (sometimes in combination), topical steroids and, in resistant cases, dapsone, thalidomide and, as a last resort, immunosuppressive agents.
Less severe SLE manifestations, such as myalgias, arthralgias, arthritis and serositis, are treated with nonsteroidal antiinflammatory drugs (NSAIDs), followed by antimalarial agents such as hydroxychloroquine, low-dose glucocorticoids and even dehydroepiandrosterone (DHEA), which at this time is available as a dietary supplement in health-food stores.
‘Lupus fatigue’ is a distressing and extremely common complaint in patients with SLE, best managed by adequate rest, a regular exercise program, and management of comorbidities such as depression and sleep deprivation.
The treatment of lupus nephritis, an important cause of morbidity and mortality in SLE, is best guided by the results of the renal biopsy. Proliferative lesions (WHO Class III or IV) are best managed by high-dose glucocorticoids and a 6-month course of monthly pulse cyclophosphamide followed by maintenance with either azathioprine, mycophenolate mofetil or, if necessary, cyclophosphamide.
Equal attention must by paid to the management of comorbidities associated with lupus nephritis (or the treatment thereof), specifically hypertension, antiphospholipid antibody syndrome, drug-induced nephropathy and diabetic mellitus.
Neuropsychiatric lupus involves a heterogeneous group of disorders, best managed by targeting the underlying cause (i.e., active SLE, thrombosis, or secondary psychiatric illness such as reactive depression).
Although leukopenia attributable to lupus flares does not require specific treatment, severe and symptomatic Coombs'-positive hemolytic anemia and thrombocytopenia (especially when <50,000 mm3) are managed with glucocorticoids, and in refractory patients, intravenous immunoglobulin, cytotoxic agents and even splenectomy.
Newer treatments, especially biological agents such as rituximab (also, anti-CD40 ligand monoclonal antibody, abatacept, interleukin [IL]-10, B-lymphocyte stimulator antagonists and neutralizing antibodies against IL-10 and C5b), as well as autologous hematopoietic stem-cell transplantation, are showing promise for the near future and are currently under evaluation.
In general, flares of SLE during pregnancy are most safely managed with glucocorticoids in the lowest dose necessary. For patients also receiving hydroxychloroquine, it is probably safer to continue the drug throughout pregnancy to prevent flares than any potential fetal toxicity associated with its use.