Beth H. Resman-Targoff
KEY CONCEPTS
Systemic lupus erythematosus (SLE) is considered a disease primarily of young women, but can occur in anyone. The prevalence and severity vary with sex, race, ethnicity, and socioeconomic factors.
Understanding the etiology of SLE and environmental factors that can initiate or exacerbate the disease may make it possible to avoid those triggers.
SLE is an autoimmune disease characterized by the presence of autoantibodies, some of which may play a role in the pathogenesis of the disease. An understanding of disease mechanisms can lead to targeted drug therapy.
SLE is a multisystem disease that can involve almost any organ and may present in many different ways. Therapy is determined by the manifestations in each patient. These may change and fluctuate in severity over time.
Lifestyle changes can modify risk factors for SLE flares and complications.
The overall goals of therapy are to prevent disease flares and involvement of other organs, decrease disease activity and prevent damage, maintain remission, reduce use of corticosteroids, and improve quality of life, while minimizing adverse effects and costs. Most patients with SLE should receive hydroxychloroquine alone or in combination with other therapy appropriate for the disease manifestations.
Pregnancy planning is essential for good outcomes. Pregnancy outcomes are best when the disease is controlled before conception. Drugs used to treat SLE may adversely affect fertility and the fetus.
Antiphospholipid antibodies are associated with arterial and venous thrombosis and obstetric complications.
Many drugs can induce a lupus-like syndrome. The manifestations and laboratory findings may be different between the traditional drug-induced lupus and that seen with use of tumor necrosis factor-alpha inhibitors.
Since SLE can present in many different ways, it is difficult to design standard response criteria. Development of appropriate criteria is essential for getting new drugs approved.
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with autoantibody production. The term “lupus” was first used to describe a skin disease in medieval times. The name may have been selected since the lesions looked like skin that had been gnawed by a wolf. In the mid-1800s, it was recognized that other organs may be affected and we now know that SLE is a multisystem disease. The common finding in SLE is production of antibodies to self-constituents.1 This is an exciting time in the management of SLE because better understanding of disease mechanisms has led to the development of new drugs. In addition, new response criteria are being developed to show efficacy of drugs, even with the background of standard therapy. This has led to the first approval of a drug for treatment of SLE in over 50 years. Despite these advances, management of this disease remains a challenge. It has a myriad of manifestations and many of the drugs used to treat it are not approved for this indication. As a result, there is no standard dosing for many of the drugs considered to be standard-of-care therapy.
EPIDEMIOLOGY
SLE is generally considered to occur most frequently in women of reproductive age in their late teens to early 40s.2 This is especially characteristic of the disease in nonwhite women. Statistics regarding SLE depend on the population studied and sampling and recruitment criteria. These have profound effects on estimates of incidence and prevalence, disease activity and severity, and mortality. The incidence is 1 to 10 per 100,000 person-years and the prevalence is 20 to 70 per 100,000 persons. Rates are 10 times higher in women than in men so overall population statistics can be rather misleading. It is affected by ethnicity, which includes genetic, geographic, cultural, social, and other aspects within a group. Rates are two to three times higher in people of African or Asian background than in the white population.3 It is also more common in Hispanics and Native Americans (called First Nations in Canada) than in whites.3,4 Most people are of mixed race, so race by itself can be difficult to analyze. Nonwhites tend to have an earlier onset, more severe disease, and a higher mortality rate, but it can be difficult to separate out the influence of socioeconomic factors and access to medical care.5 The disease tends to be more severe in men, children, and those with onset at a later age (over 50 years).3
Survival rates have improved in recent years with better therapy and earlier diagnosis and initiation of treatment. Overall SLE survival is 95% at 5 years and 92% at 10 years after diagnosis. This is reduced to about 88% at 10 years with lupus nephritis and even less than that in African Americans with lupus nephritis.6 The survival rate may be lower in men, but the small number of males in most studies makes this difficult to determine.3
ETIOLOGY
The exact etiology for SLE is unknown but many abnormal factors have been identified that appear to play a role in the disease. Some are predisposing factors and others are involved in the disease mechanisms. Categories of these elements include genetic influences, epigenetic regulation of gene expression, environmental factors, hormones, and abnormalities in immune cells and cytokines.4
The incidence of SLE is increased in affected families. Siblings of patients with SLE are 20 times more likely to develop the disease than those in a general population. Ten percent of patients with SLE have relatives with the disease.7 The concordance rate is 25% for identical twins and 2% for fraternal twins.8 The genetic predisposition to SLE is a result of the interplay of a combination of genes. In rare cases, it is thought to result primarily from a single abnormal gene.4 The major histocompatibility complex (MHC) class II alleles HLA-DR2 and HLA-DR3 are known to be linked to SLE.7 An increasing number of other gene loci are being identified as having associations with the disease.9 Gene expression is regulated by DNA methylation and histone modifications. These epigenetic changes can cause alterations that may influence SLE. Interestingly, hydralazine and procainamide, two drugs that may induce lupus, inhibit DNA methylation.4
In a genetically susceptible individual, environmental triggers can initiate the disease. It is possible that the type of trigger may influence the specific organ involvement. Cigarette smoke has many components, such as hydrazine, that may affect the immune system. Chronic smokers and former smokers are more likely to have elevated titers of anti-double-stranded DNA (anti-dsDNA) antibodies. Cigarette smoking is phototoxic and associated with cutaneous lupus.10 Ultraviolet light can cause keratinocytes in the skin to release nuclear material that can further stimulate the immune system and autoantibody production by B cells.4,10 Viruses may trigger SLE. Several studies have suggested a potential role for the Epstein–Barr virus.4 Other implicated triggers include infections, medications (including vaccines and biologics), psychological stress, silica dust, hydrazines, petroleum, solvents (such as nail polish and metal cleaners), dyes, and pesticides.10
The greater prevalence in women suggests that hormones such as estrogens and progesterones may play a role in SLE, but the presence of the X chromosome may also contribute.4 The incidence of SLE is increased in men with Klinefelter’s (XXY) syndrome and decreased in women with Turner’s (XO) syndrome.11
PATHOPHYSIOLOGY
SLE is a multisystem disease characterized by disorders of the immune system (Fig. 69-1). T and B lymphocyte activation and signaling are altered in SLE and there is abnormal clearance of apoptotic cells.8 The number of plasma cells is increased in active SLE and these cells produce autoantibodies, which can cause tissue damage.4 Antibodies directed at dsDNA are seen in about 70% of patients with SLE and only 0.5% of patients without the disease.8 The titers of anti-dsDNA may fluctuate with disease activity. Some autoantibodies may play a role in the pathogenesis of clinical features of SLE; these autoantibodies may target Ro/SSA (antigen Ro/Sjögren’s syndrome A, ribonucleoprotein complex), La/SSB (antigen La/Sjögren’s syndrome antigen B, RNA-binding protein), C1q (subunit of the C1 complement component), Sm (nuclear particles), N-methyl-D-aspartate (NMDA) receptor (amino acid released by neurons), phospholipids, nucleosomes (from apoptosis cellular debris), and histones (protein core of nucleosome). The autoantibodies can be present for many years before SLE is clinically apparent and they may be associated with specific organ involvement, such as anti-dsDNA with lupus nephritis.2,8
FIGURE 69-1 Pathogenesis of SLE. Listed genes increase susceptibility to SLE or lupus nephritis. Gene–environment interactions result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit in tissue, activate complement, cause inflammation, and lead to irreversible organ damage. Ag, antigen; C1q, complement system; C3, complement component; DC, dendritic cell; EBV, Epstein–Barr virus; HLA, human leukocyte antigen; FcR, immunoglobulin Fc-binding receptor; IL, interleukin; MCP, monocyte chemotactic protein; PTPN, phosphotyrosine phosphatase; UV, ultraviolet light. (From Hahn BH. Systemic lupus erythematosus. In: Longo DL, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. [electronic version]. 2012, Access Medicine. Chapter 319.)
Immune complexes form when antinuclear antibodies (ANA) bind to nuclear material in blood and tissues, and they can accumulate in the kidneys, skin, CNS, and other sites. They activate the complement cascade, leading to an influx of inflammatory cells and tissue injury. Antibodies to blood cells can cause cytopenias. Antibodies against phospholipids can lead to thrombosis and fetal loss. These antiphospholipid antibodies interfere with protein C and endothelial cell function, inducing tissue factor that leads to thrombus formation. They also cause platelet aggregation. The antiphospholipid antibodies bind to placental trophoblast cells and activate complement, which can lead to fetal loss.4
Antigens can interact with MHC molecules on the surface of antigen-presenting cells, such as B cells, macrophages, and dendritic cells. T cells respond to these antigens along with other receptors on the antigen-presenting cells and become activated. Examples of these paired receptors are the CD40-CD40 ligand and CD28-B7. Cytokines produced by activated T cells can stimulate B cells.8
Cytokines play multiple roles in SLE. Anti-T-cell antibodies decrease interleukin-2 production, which can increase the risk for infections by decreasing the activity of cytotoxic T cells and increasing the lifespan of autoreactive T cells. Increased T cell production of interkeukin-17 and expression of adhesion molecule CD44 may contribute to kidney and other organ damage. Plasmacytoid dendritic cells accumulate in skin and kidneys and secrete interferon-α. B-lymphocyte stimulator (BLyS), also known as BAFF or B cell activating factor of the TNF family, increases survival of B cells. Interleukin-6 promotes production of antibodies.4 The role of tumor necrosis factor-alpha (TNF-α) in SLE is unclear. In some patients it appears to be harmful, and in others, protective.12
CLINICAL PRESENTATION
SLE is an autoimmune disease that can involve almost any organ and may present in many different ways. This can make it difficult to establish a diagnosis and an extensive work-up may be needed to determine the full extent of involvement and to exclude other possible etiologies for the manifestations. More common features include involvement of the skin and mucus membranes, joints, kidneys, CNS, serous membranes, cardiovascular system, and hematologic cell lines. Fatigue and depression are frequent symptoms and can adversely affect quality of life.13 Arthritis or arthralgias are experienced by 83% to 95% of patients with SLE.7 SLE may present differently in men and women. For example, men tend to get SLE at an older age and are more likely to have renal and hematologic involvement, but have fewer dermatologic features. Race and ethnicity may also affect the specific manifestations.14
Disease manifestations fluctuate with periods of remission, flares, and progression.7 The presence of ANA may be used as a screening test for SLE. Most patients with SLE have these antibodies, but they are not specific for the disease.15
An international group of SLE researchers developed and validated new criteria for classification of SLE in 2012. These are referred to as the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria and were developed to identify patients with the disease for clinical studies. They are not intended for establishing a diagnosis in an individual patient, but may be helpful in assessing the likelihood that a patient has SLE. The widely used American College of Rheumatology (ACR) criteria were developed in 1982 and revised in 1997. The 1997 version was not validated. The SLICC criteria are more clinically relevant and sensitive than the ACR criteria. When validated, the SLICC criteria had a sensitivity of 97% and specificity of 84% compared to 83% and 96% for the ACR criteria. The number of criteria was expanded from 11 to 17 and, unlike the ACR criteria, they are divided into clinical and immunologic parameters. The ACR criteria required 4 of the 11 elements to be present, serially or simultaneously. To satisfy the SLICC criteria, a patient must still meet at least four of the elements, but now these must include at least one clinical and one immunologic criterion or the patient must have biopsy-proven lupus nephritis with positive ANA or anti-dsDNA antibodies. An abbreviated version of the SLICC criteria, with comparison to the ACR criteria, is shown in Table 69-1.15–17
TABLE 69-1 2012 Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria for Systemic Lupus Erythematosus
An international working group of SLE experts devised a consensus definition of SLE flare: “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.”18
Some skin involvement is seen in 70% to 85% of patients with SLE.19 This can be disfiguring and affect a patient’s feelings of self-esteem.10 Three main types of cutaneous lupus erythematosus have been observed. Acute cutaneous lupus erythematosus is typically seen in patients with SLE and is characterized by a malar rash over the cheeks and nose with sparing of the nasolabial folds. The arms and trunk may be involved. The manifestations usually wax and wane without scarring. Severe SLE is less common with the other forms of cutaneous lupus. Subacute cutaneous lupus erythematosus is usually photosensitive and is manifested by annular or psoriasiform plaques that usually heal without scarring. It can be accompanied by musculoskeletal complaints and patients usually have anti-Ro/SSA autoantibodies. Many subtypes of chronic cutaneous lupus erythematosus have been identified. The most common is discoid lupus, which is confined to the head and neck in about two-thirds of patients, but it can be generalized.20,21 Chronic discoid lupus is the first manifestation of SLE in up to 10% of cases. Discoid lupus progresses to SLE in about 5% to 10% of patients. It is more common in smokers and African Americans. It may be associated with scarring, scarring alopecia, malar rash, photosensitivity, oral ulcers, leukopenia, vasculitis, and chronic seizures. Chronic discoid lupus is associated with a lower incidence of arthritis, end-stage renal disease, and immunologic markers such as ANA, anti-dsDNA, and antiphospholipid antibodies.19
CLINICAL PRESENTATION
Symptoms
• Fatigue, depression, photosensitivity, joint pain, headache, weight loss, nausea/abdominal pain
Signs
• Rash, alopecia, fever, oral and nasal ulcers, arthritis, renal dysfunction, seizure, psychosis, pleuritis, pleural effusion, cardiovascular disease, pericarditis/myocarditis, heart murmur, hypertension, anemia, leukopenia, thrombocytopenia, lymphadenopathy, Raynaud’s phenomenon, vasculitis
Diagnostic Tests
• Serology: autoantibodies, antiphospholipid antibodies, complement; inflammatory markers: C-reactive protein, erythrocyte sedimentation rate; blood chemistries; complete blood count; urinalysis; lumbar puncture; renal biopsy
Lupus nephritis is present at the time of SLE diagnosis in about 35% of adult patients and 50% to 60% of patients develop it by 10 years. It is more common in African American and Hispanic patients than in whites and more prevalent in men than in women. The International Society of Nephrology/Renal Pathology Society devised a classification system for lupus nephritis based on histologic findings: Class I: minimal mesangial, Class II: mesangial proliferative; Class III: focal (less than 50% of glomeruli involved); Class IV: diffuse (50% or more of glomeruli involved); Class V: membranous; and Class VI: advanced sclerosing (at least 90% globally sclerosed glomeruli without residual activity). Patients with nephritis may also have hypertension and atherosclerosis.6
The central and peripheral nervous systems can be involved in SLE. The frequency of this involvement is around 30% to 40%, but depends on the population studied and methods for detecting the occurrence. About 50% to 60% of neuropsychiatric events appear within the first year after the diagnosis of SLE, usually during times of generalized disease activity. Mild nonspecific neuropsychiatric findings such as headache, mood disorders, anxiety, and mild cognitive dysfunction are common in SLE but may not reflect overt CNS disease activity. Findings more indicative of neuropsychiatric lupus include cerebrovascular disease (ischemic stroke and/or transient ischemic attack) and seizures in 5% to 15% of patients; severe cognitive dysfunction, major depression, acute confusional state, and peripheral nervous disorders (e.g., polyneuropathy, mononeuropathy) in 1% to 5%; and psychosis, myelitis, chorea, cranial neuropathies, and aseptic meningitis in <1% of patients. Risk factors include general SLE disease activity, prior neuropsychiatric events, and presence of moderate-to-high titers of antiphospholipid antibodies. It is important to assess contributing factors and to rule out other possible etiologies of these manifestations. The diagnostic approach will vary depending on the clinical presentation and preliminary findings, but can include a thorough history and physical, lumbar puncture with cerebrospinal fluid analysis (mostly to exclude infection), electroencephalogram, serology, complete blood count, blood chemistries, neuropsychological assessment of cognitive function, nerve conduction studies, and magnetic resonance imaging.22
Not only are there cardiac manifestations of SLE, such as pericarditis and myocarditis, but patients with SLE are also at increased risk for cardiovascular disease with accelerated atherosclerosis. This is probably related to the chronic inflammation associated with the disease and adverse effects of the drugs (e.g., high-dose corticosteroids) used to treat it.2
TREATMENT
Systemic Lupus Erythematosus
Treatment of SLE is determined by the patient’s symptoms and organ involvement.
Desired Outcomes
The overall goals of therapy are to prevent disease flares and involvement of other organs, decrease disease activity and prevent damage, maintain remission, reduce use of corticosteroids, and improve quality of life, while minimizing adverse effects and costs. Success in achieving these outcomes depends on disease severity and the type and extent of organ impairment. In general, the prognosis is better if lupus is limited to skin and musculoskeletal findings. The worst prognosis is seen with renal or CNS involvement.7 Many of the desired outcomes have been observed with antimalarials, although most patients require additional therapy.23 Survival and quality of life have improved with better understanding of disease mechanisms and new therapeutic options. Mortality is affected by SLE disease activity, cardiovascular risks, and infections.
General Approach
Patients with SLE should be counseled about the importance of lifestyle modifications such as protection from the sun, smoking cessation, exercise, and weight control. The need for immunizations should be assessed with consideration of appropriate timing with respect to immunosuppressive use. The effects of disease activity and treatment on pregnancy outcomes should be discussed. Patients should be evaluated and treated for any comorbidities such as hypertension, hyperlipidemia, and depression. Mild symptoms can be managed with nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen.24Antimalarial drugs have numerous beneficial effects in SLE and many experts feel that most patients with the disease should always receive one of these drugs.23 Corticosteroids are used to treat most forms of SLE and up to 80% of patients receive low doses indefinitely as maintenance therapy. The need for osteoporosis prevention should be assessed.25 If the above therapy is ineffective or major organs are involved, immunosuppressive or immunomodulatory drugs are added.24 The specific treatment is determined by the organs involved and severity of the disease.
Nonpharmacologic Therapy
Patient perceptions of well-being and quality of life are affected not only by disease activity, but also by social support, coping mechanisms, feelings of helplessness, and abnormal illness-related behaviors.3 Good social support can improve outcomes, in part by making it easier for patients and their families to navigate the healthcare system and utilize resources. Counseling and support groups may help patients’ mental well-being and coping mechanisms, but do not affect SLE disease activity. Aerobic cardiovascular exercise may help decrease patients’ risk for cardiovascular events and osteoporosis and may also improve fatigue and sleep disturbances, which are frequently experienced in SLE.26
Since photosensitivity is common in SLE, patients should protect themselves from the sun by wearing protective clothing and hats and using sunscreens. They should avoid tanning salons.20 The FDA issued new regulations for testing and labeling of sunscreens that took effect in 2012. Sunscreens labeled as broad spectrum protect against ultraviolet A and B radiation. They have sun protection factors (SPFs) of 15 to 50+.27 Patients with SLE should use sunscreens with high SPF values and apply them every 2 hours while in the sun.20
Patients should be counseled to stop smoking. Smoking cessation is important, not only because it decreases cardiovascular risk, but because smoking can exacerbate SLE and diminish the effectiveness of antimalarials.28Smokers also have a higher incidence of active rashes with skin damage and scarring.29
Pharmacologic Therapy
Treatment is determined by the manifestations of SLE in the individual patient. It consists of a combination of immunosuppression and symptomatic and supportive therapies. The only drugs approved by the FDA for treatment of SLE are aspirin, prednisone, hydroxychloroquine, and belimumab. The use of other drugs for SLE, even those considered “standard of care,” is considered to be “off-label” use. For many of these drugs, the optimal doses and duration of therapy for induction and maintenance of response in SLE have not been determined.
Organization or expert task force treatment recommendations have been published for lupus nephritis, neuropsychiatric lupus, and antiphospholipid antibody carriers.6,22,30 A committee of the ACR developed guidelines for screening, treatment, and management of lupus nephritis. All patients with nephritis should receive hydroxychloroquine to reduce damage and flares. An angiotensin-converting enzyme inhibitor or angiotensin receptor blocker can reduce proteinuria by about 30% in those with proteinuria of 0.5 g/day or more, and delay progression of renal disease. Blood pressure should be maintained at no more than 130/80 mm Hg. Patients with a low-density lipoprotein cholesterol greater than 100 mg/dL (2.59 mmol/L) should receive a statin to prevent accelerated atherosclerosis. More specific treatment is based on the type of nephritis. The first two classes, minimal mesangial and mesangial proliferative lupus nephritis do not usually need immunosuppressive therapy. Focal and diffuse lupus nephritis (Classes III and IV) are treated similarly with aggressive use of glucocorticoids and immunosuppressive therapy. Figure 69-2 shows the induction regimens for these patients and the levels of evidence to support the recommendations. Patients with a combination of Class V with III or IV would be treated similarly to those with only III or IV. The initial cyclophosphamide or mycophenolate mofetil therapy should be continued for 6 months unless proteinuria or serum creatinine worsens by 50% or more at 3 months (Level A evidence). After 6 months of induction therapy, patients who have improved can be maintained on mycophenolate mofetil or azathioprine, with low doses of corticosteroids if needed. Patients with pure Class V, membranous lupus nephritis, and nephrotic range proteinuria of more than 3 g/day should receive induction therapy with mycophenolate mofetil 2 to 3 g/day with prednisone 0.5 mg/kg/day for 6 months (Level A evidence). Those who improve can be maintained on mycophenolate mofetil 1 to 2 g/day or azathioprine 2 mg/kg/day. Patients who do not respond should be treated with cyclophosphamide 500 to 1000 mg/m2/month for 6 months with IV pulse glucocorticoids, followed by prednisone 0.5 to 1 mg/kg/day. Patients with advanced sclerosing lupus nephritis (Class VI) should be considered for renal replacement therapy.6
FIGURE 69-2 American College of Rheumatology guidelines for therapy for Class III/IV lupus nephritis. (AZA, azathioprine; BSA, body surface area; GC, glucocorticoids; MMF, mycophenolate mofetil; *, preference of MMF over cyclophosphamide (CYC) in patients who desire to preserve fertility; †, recommended background therapies discussed in text.) (Modified from Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res [Hoboken] 2012;64:797–808. Figure 2, Page 800.)
A task force of the European League Against Rheumatism (EULAR) devised recommendations for the management of neuropsychiatric lupus. Treatment depends on the manifestations. Symptomatic therapy (e.g., anticonvulsants, antidepressants) should be given as needed. More specific treatment depends on whether the problem is determined to be inflammatory or thrombotic or both. If there is inflammation or neurotoxic damage in the presence of generalized SLE activity, glucocorticoids alone or in conjunction with immunosuppressive drugs such as azathioprine or cyclophosphamide should be given (Strong evidence). If the condition does not respond, other treatments such as plasma exchange, IV immunoglobulin, or rituximab can be tried. If the problem is related to moderate-to-high titers of antiphospholipid antibodies and/or thrombosis, anticoagulants and/or inhibitors of platelet aggregation should be used (Sufficient evidence).22
For patients with intermittent joint pain associated with SLE, NSAIDs are good initial therapy. If the pain is more severe or persistent, prednisone in a dose of 10 mg/day or less in combination with hydroxychloroquine should be instituted. Intraarticular corticosteroid injections can be used for localized joint pain. If this therapy is inadequate, methotrexate can be added to hydroxychloroquine therapy. For patients who fail or are intolerant of these therapies, mycophenolate mofetil or azathioprine can be tried. If alternative treatment is needed, leflunomide, belimumab, rituximab, abatacept, or TNF-α inhibitors may be considered.31
The first step in management of cutaneous lupus erythematosus is counseling patients to protect themselves from ultraviolet light as described above.20 Choice of drug treatment is based on the extent and severity of involvement. Topical corticosteroids are commonly used and may relieve symptoms such as itching or burning, but may not provide adequate clearing of lesions when used alone.20 The choice of corticosteroid depends on the location of application. Low potency corticosteroids (e.g., fluocinolone acetonide 0.01% and hydrocortisone butyrate 1%) should be used on areas with thin skin such as the face, mid-potency (e.g., triamcinolone acetonide and betamethasone valerate) for trunk and extremities, and high potency (e.g., clobetasol propionate) for thick-skin areas such as scalp, soles, and palms. Creams or ointments are used on the body, and foams or solutions on the scalp.21 Intralesional corticosteroids may be used in discoid lupus, but should not be repeated more often than every 4 to 6 weeks.20 To avoid the adverse effects of topical corticosteroids, such as skin atrophy, telangiectasias, and rosacea, the duration of therapy should be limited. Alternatively, topical calcineurin inhibitors may be used instead. Pimecrolimus is more lipophilic than tacrolimus and has greater affinity to the skin.20 Antimalarials have photoprotective effects and are commonly used in the management of cutaneous lupus. If hydroxychloroquine alone is ineffective, quinacrine, available from compounding pharmacies, may be added. For refractory disease, systemic immunosuppressive (e.g., corticosteroids, methotrexate, mycophenolate mofetil, or azathioprine) or immunomodulatory drugs (e.g., dapsone or thalidomide) may be added. The evidence to support their use in management of cutaneous lupus is mainly on case reports rather than controlled studies. The choice of agents may be guided by other organ involvement.21
Specific Drug Classes
Dosing information for selected drugs is shown in Table 69-2. Since most of the drugs used to treat SLE are not FDA-approved for that indication, the doses given are based on other uses for those drugs. Table 69-3 lists adverse effects and drug monitoring parameters. Selected issues concerning the drugs are discussed below.
TABLE 69-2 Dosing of Drugs Used to Treat Systemic Lupus Erythematosus
TABLE 69-3 Monitoring of Drugs Used to Treat Systemic Lupus Erythematosus
Nonsteroidal Antiinflammatory Drugs NSAIDs are used as first-line treatment for arthritis, musculoskeletal complaints, fever, and serositis.32 Low-dose aspirin is used in patients with antiphospholipid antibodies.30 One concern with use of NSAIDs is that they can decrease renal function, which can complicate evaluation of lupus nephritis. They have the potential to increase cardiac events in patients who already are at elevated risk. Other adverse effects include hepatotoxicity, GI bleeding, and aseptic meningitis.32
Corticosteroids Corticosteroids as monotherapy or as adjuncts to other treatment can control flares and maintain low disease activity in SLE. Their effects have a rapid onset, whereas other therapies may take months or over a year to achieve their maximum benefits. The corticosteroids can be used topically or systemically. Although corticosteroids have been used in the management of SLE since the 1950s, optimal doses have not been determined. High doses given in a pulse IV administration regimen are used to treat flares and quickly reduce inflammation. Doses should slowly be tapered down to the lowest effective dose. Corticosteroids are the foundation for treatment of most forms of SLE.25
High doses of systemic corticosteroids are associated with infections, myopathy, psychological disturbances, osteonecrosis, and stroke.25 Psychiatric disease, mostly mood disorder, occurs in 10% of patients receiving prednisone doses of 1 mg/kg or higher.22 Common side effects of low (less than 7.5 mg prednisone/day) to moderate (7.5 to 30 mg/day) doses are shown in Table 69-3. Although higher doses may be divided, single morning doses may be associated with fewer adverse effects and less adrenal suppression. Chronic use of any dose is associated with coronary artery disease, cataracts, and osteoporosis.25Corticosteroids increase catabolism of 25(OH) vitamin D and 1,25(OH)2 vitamin D. Osteoporosis prophylaxis is often found to be inadequate.33 To avoid adrenal insufficiency, patients on chronic corticosteroid therapy should not have treatment stopped abruptly and they may need increased doses at times of stress such as surgery. Prolonged use of topical corticosteroids can lead to atrophy of the skin and telangiectasias (small dilated blood vessels).25
Antimalarials The antimalarials chloroquine and hydroxychloroquine have long been used in rheumatology practice. Hydroxychloroquine is thought to have fewer adverse reactions and is the preferred drug. In the past, hydroxychloroquine was mainly used for skin and joint manifestations of SLE, but now many believe that all patients with SLE should receive hydroxychloroquine. There is high quality evidence that it decreases disease activity and improves survival; moderate quality evidence that it increases bone mineral density and has protective effects against thrombosis and irreversible organ damage; and low quality evidence that it reduces severe flares, enhances the response to other drugs in patients with nephritis, has a beneficial effect on lipids, and protects against cancer. It can allow corticosteroid doses to be decreased. When given to patients with some findings consistent with SLE, it can delay the time for them to fully meet criteria for the disease.23 Patients receiving hydroxychloroquine often have disease flares when the drug is discontinued.
Hydroxychloroquine has antiinflammatory, immunomodulatory, and antithrombotic effects. It reduces concentrations of inflammatory cytokines such as interleukins 1, 2, and 6 and TNF-α. It inhibits antigen processing and presentation, and T cell signaling. In addition, it decreases activation of toll-like receptors, which are important in the pathogenesis of antiphospholipid syndrome (APS). It reduces red blood cell sludging, blood viscosity, and platelet aggregation.34 It also delays ultraviolet light absorption and may decrease the number of skin antigen-presenting cells.35 Finally, it may reduce cardiovascular risk factors such as hyperlipidemia and diabetes mellitus.34 The LUMINA (LUpus in MInorities, NAture versus nurture) database was initiated in 1994 to look at differences in SLE outcomes based on ethnic backgrounds. It included African Americans, Hispanics, and Caucasians. Some findings based on study of this cohort are that hydroxychloroquine may delay the occurrence of integument damage (severe skin damage including scarring, ulcers, and scarring alopecia), decrease accrual of damage, and improve survival.35,36
Hydroxychloroquine activity correlates with blood concentrations over 1000 ng/mL, but this is not routinely monitored.37 The drug has a very long elimination half-life that exceeds 40 days.38 Smoking may interfere with the metabolism of hydroxychloroquine by inducing cytochrome P450 enzymes and thus decrease its effectiveness.35
The frequency of adverse effects with hydroxychloroquine is low and they are usually mild. Most common are GI and skin reactions. The main concern is retinal toxicity, but the incidence is low and less than that seen with chloroquine.21,23 The incidence increases to 1% in patients receiving the drug for more than 5 years or who have received a cumulative dose of 1000 g. Other risk factors are daily doses more than 400 mg or 6.5 mg/kg ideal body weight, advanced age, or patients with kidney or liver dysfunction or preexisting retinal or macular disease. The retinal damage has a characteristic bull’s-eye appearance on funduscopic exam and is irreversible. Early recognition of damage may minimize vision loss. The current monitoring recommendations are to have several baseline screening tests including visual fields, then after 5 years, begin annual exams unless the patient is considered to be at high risk, in which case yearly testing would not be postponed. If there are changes suspicious for toxicity, the drug should be stopped, or, after consultation with the patient about risks of blindness, exams should be repeated every 3 to 6 months until the diagnosis is confirmed.37
Clinical Controversy…
Belimumab is an exciting new drug for the treatment of SLE, but its approval trials excluded patients with severe active lupus nephritis or CNS lupus. Results also suggested that the drug may not be beneficial for African Americans with SLE. More evidence is needed to determine the role of belimumab in treatment of these patients.
Biologic Agents Since autoantibody formation is an important feature of SLE, B cells make a logical target for SLE therapy. BLyS, or B-lymphocyte stimulator, is a cytokine that is important for B cell survival, maturation, and differentiation. Belimumab is a fully human IgG1-λ monoclonal antibody that binds to soluble BLyS, which prevents BLyS from binding to receptors on B cells and promotes apoptosis of B lymphocytes. Belimumab is FDA-approved for treatment of autoantibody-positive active SLE in addition to standard therapy. It is the first drug approved by the FDA in over 50 years for management of SLE.39 Approval of belimumab was based on two international phase III trials: BLISS-76, conducted primarily in Western Europe and North America, and BLISS-52, which was carried out in Eastern Europe, Latin America, and the Asia-Pacific region. These trials had strict entry criteria and used the new SLE Responder Index (SRI) assessment criteria. For both studies, the primary efficacy endpoint was the SRI at 52 weeks. Entry requirements included age ≥18 years old, positive ANA or anti-dsDNA, and active SLE (SELENA-SLEDAI [measure of disease activity] score ≥6) while receiving standard treatment (prednisone, NSAIDs, antimalarials, and/or immunosuppressives [but not cyclophosphamide or other biologics]). Patients had to be on stable therapy for at least 30 days. The most common organ systems involved were musculoskeletal and mucocutaneous. Patients with severe active lupus nephritis or CNS lupus were excluded. Patients received belimumab 1 mg/kg, 10 mg/kg, or placebo by IV infusion every 2 weeks for two doses, then every 4 weeks, in addition to their standard therapy. There were restrictions on concomitant medications, and those became stricter as the studies progressed. The response rate was significantly higher in the group receiving belimumab 10 mg/kg as compared to placebo in both studies.39 A post-hoc analysis of SRI response in patients of African descent showed that they did not benefit from belimumab and actually had lower SRI scores than those receiving placebo.40
Clinical Controversy…
There is conflicting evidence regarding the use of rituximab for SLE treatment. Although many believe it is effective, trials have not proven this. The discrepancy may be due to inadequate assessment criteria, selection of study population, differences in efficacy across patient subgroups, or other problems with study designs.
Rituximab is a chimeric monoclonal antibody directed at the CD20 antigen on B cells.41 Although many case reports and open-label trials have shown benefits of rituximab in treatment of SLE, randomized, placebo-controlled trials have not. The largest of these were the EXPLORER (Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus) trial which evaluated patients with extrarenal involvement treated with rituximab and immunosuppressives and the LUNAR (LUpus Nephritis Assessment with Rituximab) trial that examined use of rituximab with mycophenolate mofetil and corticosteroids in patients with lupus nephritis. Failure to show significant benefit could be due to the short duration of the trials or the choice of endpoints. Further improvement has been observed in the second year of therapy. Exploratory analyses of specific patient subgroups or use of different response criteria suggested some benefit. Rituximab may be more effective in patients of African descent with lupus nephritis than those of other races, or in combination with cyclophosphamide instead of mycophenolate mofetil. It may serve as an alternative therapy in treatment of refractory lupus nephritis, severe hematological lupus, and some CNS manifestations of the disease.41,42
Other drugs targeting B cells are being investigated in SLE. Examples of these are epratuzumab, which targets the CD22 cell surface marker on mature B cells, and atacicept which blocks both BLyS- and APRIL (a proliferation-inducing ligand)-mediated B cell stimulation.43 Other biologic agents have been tried in SLE with varying degrees of success, such as tocilizumab, which inhibits interleukin-6, and abatacept, which inhibits T cell costimulation.32The observed efficacy of drugs may depend on the definition of response used. Interestingly, a study of abatacept for lupus nephritis failed to show efficacy, but when other investigators applied endpoint criteria used in different studies of the disease to that data, very different results were observed.44
As discussed later, there is concern about TNF-α inhibitors inducing lupus. However, induction therapy with infliximab may confer long-lasting benefits in patients with lupus nephritis. When TNF-αinhibitors are used to treat lupus arthritis, patients respond but relapse within a few months after the drug is stopped.45 Biologic drugs should not be combined.
Immunosuppressive Drugs Cyclophosphamide has long been used to treat severe organ involvement in SLE such as lupus nephritis, CNS lupus, lung disease, and severe systemic vasculitis.32,46 Its role in therapy is being redefined because of the availability of newer drugs, as discussed elsewhere in this chapter. Response rate and dosing requirements may vary with patient race. Cyclophosphamide is an alkylating agent that causes crosslinkage of DNA leading to cell death. It may also suppress B cells and IgG production, and decrease production of adhesion molecules and cytokines. Cyclophosphamide has an oral bioavailability of 75% to 100%. It is a prodrug that is metabolized to active and inactive metabolites via the cytochrome P450 enzyme system. Cyclophosphamide is primarily cleared by the liver, but its active metabolites may persist in renal failure.47
With cyclophosphamide, there are concerns about the potential for hemorrhagic cystitis and bladder cancer due to acrolein, a metabolite of the drug that concentrates in the bladder. It is thought that the risk is greater with oral administration, higher cumulative doses, and in smokers. The association with intermittent pulse IV doses in SLE patients is less clear. One approach to decreasing these adverse effects is hydration and frequent voiding. With oral administration, patients are advised to take the drug in the morning and to drink fluids for several hours. Adherence is not good with this regimen. With IV administration, IV fluids are begun before administration of the cyclophosphamide and continued for several hours after. Patients are encouraged to maintain oral hydration for 72 hours. Another method to decrease bladder toxicity is to use sodium-2-mercaptoethane sulfonate (mesna), which binds acrolein and prevents its harmful effects on the bladder. Although mesna is sometimes used with high-dose cyclophosphamide, it is only FDA-approved for use with ifosfamide. Use of mesna with daily oral cyclophosphamide is expensive and awkward based on available dosage forms. The recommended mesna regimen with IV pulse doses of cyclophosphamide is to give IV doses, each equivalent to 20% of the cyclophosphamide dose, 15 to 30 minutes before the cyclophosphamide, then 4 and 8 hours after. Since oral mesna is about 50% bioavailable, the 4- and 8-hour mesna doses after cyclophosphamide may be given orally, each in doses equivalent to 40% of the administered dose of cyclophosphamide.47 In practice, a variety of mesna regimens are used.
Mycophenolic acid (MPA) reversibly inhibits the enzyme inosine 5-monophosphate dehydrogenase (IMPDH), which is important for de novo synthesis of purine (guanosine) nucleotides. This inhibits proliferation and differentiation of lymphocytes. The drug also has other immunomodulating effects such as induction of activated T cell apoptosis, inhibition of adhesion molecule expression, and antifibrotic and antiproliferative effects on cells such as fibroblasts, dendritic cells, and vascular smooth muscle cells.48
Mycophenolate mofetil is hydrolyzed to MPA, its active form. The mofetil salt has greater bioavailability. MPA is bound to albumin, so unbound drug concentrations can be affected by changes in albumin. MPA is glucuronidated in the liver to an inactive metabolite, mycophenolic glucuronide. The metabolite undergoes enterohepatic recycling, with conversion back to the active form.48
Mycophenolate mofetil has been most studied in treatment of lupus nephritis. It has been shown to be at least as effective as cyclophosphamide for induction therapy and as azathioprine for maintenance treatment. The Aspreva Lupus Management Study (ALMS) was a multinational study of lupus nephritis in 370 patients. The 6-month induction phase showed mycophenolate mofetil to be equivalent in efficacy to monthly IV pulse doses of cyclophosphamide, including in a small group of patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min (0.5 mL/s).48 The response to therapy at 6 months correlated with the baseline complement C4 concentration, time since diagnosis of lupus nephritis, and eGFR. Normalization of complement C3 and/or C4 and reduction in proteinuria of at least 25% at 8 weeks also predicted renal improvement at 6 months.49 In the 36-month maintenance phase, mycophenolate mofetil was superior to azathioprine in maintaining renal response to treatment and preventing disease relapse. Although adverse events occurred in more than 97% of patients in both groups, more patients receiving azathioprine withdrew from the study due to toxicity than those receiving mycophenolate mofetil.50 The MAINTAIN trial did not find a difference in the rate of renal flare with mycophenolate mofetil compared to azathioprine 5 years after induction with IV cyclophosphamide. The difference in these results compared to the ALMS trial may be due to the difference in populations studied. The MAINTAIN trial studied 105 predominantly white European patients, whereas the larger ALMS trial included a more racially diverse population.48
Mycophenolate mofetil may also be useful for other manifestations of SLE such as arthritis, cutaneous lupus, and hematologic involvement, including hemolytic anemia and thrombocytopenia.48
The most common adverse effects observed with mycophenolate mofetil are GI, including nausea, vomiting, and diarrhea. These may be severe enough to require discontinuation of therapy. Hematologic effects such as red cell aplasia may also be seen. The side effects may be diminished with a reduction in dose. Use of an enteric-coated form may decrease GI symptoms. Numerous congenital malformations have been reported with mycophenolate mofetil and it is contraindicated in pregnancy.48
Azathioprine is a purine analog that is metabolized to mercaptopurine. It inhibits DNA synthesis and prevents immune cell proliferation. Mercaptopurine is inactivated by thiopurine methyltransferase (TPMT). If activity of that enzyme is low, patients may experience severe toxicity such as myelosuppression and hepatotoxicity. The metabolism of azathioprine and mercaptopurine is also inhibited by allopurinol and febuxostat. If the combination of these drugs is to be used, a reduction in dose is required.51 Azathioprine is less effective than cyclophosphamide for induction therapy in lupus nephritis, but it can be useful as an alternative to mycophenolate mofetil for maintenance treatment.6 Azathioprine may also be used for SLE-related arthritis, serositis, mucocutaneous manifestations, and for hematologic involvement. It has steroid-sparing effects, allowing use of lower doses of corticosteroids.32,46
Methotrexate is an inhibitor of folic acid reductase, which is needed for DNA synthesis and cell growth. Its toxicities are reduced by administration of folic acid. It is important to note that it is dosed once weekly in the management of SLE. It is used for arthritis and skin disease and as a steroid-sparing drug.32
Numerous other immunosuppressive drugs have been used in SLE, especially in patients who have contraindications to use of the agents already discussed or who cannot tolerate them, or those whose disease is refractory to conventional treatment.
Alternative Treatments
Studies have shown that SLE patients receiving conventional treatment frequently feel they have unmet needs. Often these are psychosocial and may include anxiety or depression. These needs can lead patients to try alternative therapies. It is important for healthcare providers to have an open dialogue with patients about these therapies so that patients will report them. This allows practitioners to monitor for interactions with other treatments and to guide patients to therapies with greater potential for benefit and less for harm.26
The ACR has defined complementary and alternative medicine as treatments, products, and practices that are outside the realm of traditional allopathic medicine. In general, these have not been evaluated in randomized controlled trials involving SLE patients.26
Concentrations of dehydroepiandrosterone (DHEA), a weak androgen, are typically decreased in SLE. Some small studies have suggested that DHEA supplementation may offer some limited benefit for health-related quality of life (HRQoL) in SLE.26
Clinical Controversy…
Vitamin D promotes bone and heart health and contributes to immune response; deficiency may be associated with greater SLE disease activity, flares, and fatigue. Concentrations of vitamin D are commonly decreased in SLE, and it has been suggested that all patients with the disease should receive vitamin D supplementation. However, not all experts agree and appropriate target vitamin D concentrations are yet to be determined.
Vitamin D concentrations are decreased in SLE, especially in patients with high disease activity and those with darker skin pigmentation (e.g., African Americans). A contributing factor to the deficiency is that patients are told to protect themselves from sunlight because of the photosensitivity that accompanies SLE.33 This can not only affect bone health, but there are some data showing that low concentrations of vitamin D may also be associated with greater SLE disease activity, flares, and fatigue.52–54 Vitamin D plays a role in the immune response, including suppression of T lymphocyte proliferation, inhibition of immunoglobulin production by B cells, and effects on dendritic cells, which affect protective immunity and self-tolerance. Vitamin D also has cardioprotective effects and may decrease cancer risks.33 Some experts suggest that most patients with SLE should receive vitamin D supplements of at least 400 IU/day of vitamin D3.20 One recommendation is to check a baseline 25(OH) vitamin D concentration with a current goal of 30 ng/mL (75 nmol/L). An optimal goal has not yet been determined. The concentration should be rechecked 3 months after a change in vitamin D dosing since that is the time required to reach steady state.33
Special Populations
Pregnancy and Contraception 
Pregnancy planning with assessment of risk factors is key for achieving good outcomes for women with SLE and healthy babies. Timing of pregnancies with respect to disease activity and use of teratogenic medications make contraception counseling very important. Cyclophosphamide therapy is associated with ovarian failure and infertility. This is especially of concern in older women who wish to conceive. Estrogen-containing oral contraceptives are associated with SLE flares and thrombosis. Although recent studies did not show an association with disease exacerbation, the results may be influenced by study inclusion and exclusion criteria.55Estrogen replacement may increase the risk of thrombosis in postmenopausal women.10 Progesterone-only contraceptives may be used but the risk of osteoporosis increases after 2 years of use. Intrauterine devices or barrier methods with spermicides may be better choices for contraception.55
Pregnancy during SLE is considered to be high risk. The risk of maternal mortality, cesarean delivery, preterm labor, and preeclampsia and the risk of thrombotic, infectious, and hematologic complications are increased. Fetal loss and growth retardation may relate to placental pathology with vascular changes and thrombi, even in the absence of antiphospholipid antibodies. Complement activation may contribute to these occurrences. Preeclampsia occurs in 10% to 25% of women with SLE and is defined as hypertension (BP >140/90) and proteinuria (>300 mg/24 h) that develop for the first time after 20 weeks of gestation. This can be difficult to distinguish from lupus nephritis. The risk for preeclampsia and fetal loss may be decreased with daily use of low-dose aspirin.56 Flares during pregnancy may be difficult to identify since they may share characteristics of a normal pregnancy. The complications are more likely in patients with active disease, especially lupus nephritis. If the mother has anti-Ro/SSA or anti-La/SSB antibodies, the fetus is at risk for neonatal lupus with rash and cardiac abnormalities including heart block. Treatment of pregnant women with antiphospholipid antibodies is discussed below. Pregnancy should be discouraged in patients with severe pulmonary hypertension, advanced renal insufficiency, severe restrictive lung disease, heart failure, or a history of severe preeclampsia. It also is not advised within 6 months of a severe SLE flare, active lupus nephritis, or a stroke. The best pregnancy outcomes are observed in patients who have had inactive disease for at least 6 months prior to the pregnancy. Drugs used to control the SLE should be those such as hydroxychloroquine, which can be continued throughout the pregnancy and may decrease the incidence of flares. Any potentially teratogenic drugs (e.g., methotrexate, leflunomide, mycophenolate, cyclophosphamide, and thalidomide) should be stopped at least 3 months before attempting pregnancy. Leflunomide should be removed through the oral cholestyramine elimination procedure (8 g three times a day for 11 days with confirmation of undetectable serum concentrations) prior to conception. Close monitoring and disease management of the mothers and fetuses are essential during pregnancy. The risks of drug use and harmful effects of disease flare both need to be considered. If a flare occurs and an immunosuppressive drug is required during the pregnancy, azathioprine may be considered, since the fetal liver is unable to metabolize it to its active form.55 The dose should not exceed 2 mg/kg/day.6 If corticosteroids are needed, maintenance doses should be kept at the equivalent of prednisone 10 mg daily or less to decrease the risk of gestational diabetes mellitus, infections, and premature rupture of membranes.25,55 Fluorinated corticosteroids (such as dexamethasone or betamethasone) should be avoided unless they are being used to treat the fetus, since they cross the placenta. Cyclophosphamide should only be used during pregnancy if alternatives failed and the mother’s life is in danger. If treatment of hypertension is needed, methyldopa and labetalol are preferred with nifedipine considered as an alternative. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may damage the fetal kidneys and cause fetal loss. Diuretics are generally avoided but if one is needed, furosemide is preferred.55
SLE–Antiphospholipid Syndrome Overlap 
The antiphospholipid antibodies consist of anticardiolipin, anti-β-2-glycoprotein I, and lupus anticoagulant and they can promote clotting and inflammation.57The diagnosis of APS requires clinical and laboratory features. The clinical aspects are vascular events such as venous or arterial thrombi and/or obstetric complications. The obstetric complications meeting the criteria are three or more unexplained consecutive miscarriages before the tenth week of gestation, one or more unexplained deaths of fetuses at or beyond the tenth week of gestation, and one or more births of infants before the 34th week of gestation associated with eclampsia or severe preeclampsia.57 Adverse pregnancy outcomes after 12 weeks of gestation are especially associated with the presence of lupus anticoagulant.58 Laboratory criteria are the presence of antiphospholipid antibodies on two separate occasions, 12 weeks apart.59 Antiphospholipid antibodies are found in about 40% of patients with SLE, but less than 40% of those experience thrombotic events.57 Patients with lupus anticoagulant or persistently positive anticardiolipin at medium-high titers are at high risk for thrombosis, and those with all three antibodies (triple positivity) are at highest risk. Patients with isolated, intermittently positive anticardiolipin or anti-β2-glycoprotein I at low-medium titers are considered to be at low risk. Patients with thrombosis often have other cardiovascular risk factors (such as hypertension, hyperlipidemia, smoking, or use of estrogen-containing medications) or an underlying autoimmune disease such as SLE. It is recommended that any modifiable factors be controlled. In deciding choice, intensity, and duration of treatment, the clinician should balance benefits with the patient’s risk of bleeding. Consideration should also be given to whether thrombotic events are associated with identified transient precipitating factors. An international group of physicians who had clinical and research experience with APS reviewed the literature and developed consensus guidelines for management of thrombosis in patients with antiphospholipid antibodies (Table 69-4).30
TABLE 69-4 Recommendations for Thromboprophylaxis in Patients with Systemic Lupus Erythematosus and Antiphospholipid Antibodies
Patients with antiphospholipid antibodies may also have a false-positive test for syphilis (rapid plasma reagin).15 Other common manifestations of APS are cognitive impairment, thrombocytopenia, stroke or transient ischemic attack, migraine, and livedo reticularis.57
It is not clear how to treat pregnant women with antiphospholipid antibodies. Those with no history of thrombosis who have experienced early fetal loss may be treated with low-dose aspirin (81 mg) alone or in combination with prophylactic doses of heparin or low-molecular-weight heparin.57 Not only does heparin have anticoagulant effects, but it also can inhibit complement activation.4 Those without thrombosis who have had later miscarriages or premature births associated with eclampsia or preeclampsia may receive low dose aspirin plus prophylactic or intermediate doses of heparin or prophylactic doses of low-molecular-weight heparin. Pregnant patients with APS and a history of thrombosis should receive low-dose aspirin with therapeutic doses of heparin or low-molecular-weight heparin. Warfarin should be avoided during pregnancy; it is teratogenic between 6 and 12 weeks gestation and increases the risk of fetal bleeding after 12 weeks.57 If low-molecular-weight heparin is used, it should be switched to unfractionated heparin 4 weeks before the anticipated delivery date. The heparin should be stopped at the start of labor or 8 hours before a planned cesarean delivery.55 All women with APS should receive anticoagulation with prophylactic doses of heparin, low-molecular-weight heparin, or warfarin for 4 to 6 weeks postpartum. Both heparin and warfarin are safe during breastfeeding.57
For patients who do not respond to conventional APS therapy or for whom it is contraindicated, alternative therapies include other platelet inhibitors, new oral anticoagulants, hydroxychloroquine, statins, and rituximab.57
The most severe form of APS is called catastrophic and is associated with widespread thrombosis, multiorgan failure, and greater than 50% mortality.57
Drug-Induced Lupus 
About 10% of cases of SLE can be attributed to drugs. These are idiosyncratic reactions precipitated by the interplay of genetic predisposition, concurrent illnesses, environmental factors, and other drugs or foods. Various pathophysiologic mechanisms have been proposed for different drugs in inducing lupus. Most drugs are small molecules that can induce an immune response by binding to larger molecules such as proteins, a process called haptenization. Another proposed mechanism is interfering with macrophage uptake of apoptotic or necrotic cells, leading to accumulation of nucleosomes that can be targets for anti-DNA antibodies.60
Because drug-induced lupus can be so diverse in its manifestations, there are no standard diagnostic criteria. The diagnosis is based on lupus-like findings in a patient with no history of the disease and the temporal relationship with the drug, including onset after initiation and loss of manifestations within weeks to months after the drug is discontinued. The time-frame, however, can be variable.60
Many drugs of varied classes have been implicated. The drugs considered to have the highest risk for inducing traditional drug-induced lupus are procainamide (20%) and hydralazine (5–8%), especially with hydralazine doses over 200 mg per day. Common manifestations include arthralgias, arthritis, and myalgias. Constitutional symptoms such as fever, fatigue, and weight loss are common, but the incidence is about one-half that seen with idiopathic SLE. Other clinical features include rash, serositis (pleuritis, pericarditis), hematologic abnormalities, and hepatosplenomegaly. Glomerulonephritis and neuropsychiatric symptoms are rare in drug-induced lupus. The incidence and types of reactions vary depending on the offending drug. Laboratory abnormalities associated with drug-induced lupus include positive ANA (99%) and antibodies to histones (96%). Other antibodies such as anticardiolipin (5 to 20%), anti-dsDNA (less than 5%), and antineutrophil cytoplasmic antibodies (ANCA) may be seen with some drugs. A drug with moderate risk for lupus is quinidine. The incidence of quinidine- and procainamide-induced lupus is declining because of decreased prescribing of the drugs and use of lower doses. The other almost 100 drugs of many different classes that have been implicated are considered to be of low risk. One that affects younger patients, including children, is minocycline.60 Other drugs with well-established links to lupus are isoniazid, methyldopa, and chlorpromazine.10 A variant of the syndrome is drug-induced subacute cutaneous lupus, which has been associated with calcium channel antagonists, thiazide diuretics, angiotensin-converting enzyme inhibitors, and terbinafine. The mean age for this syndrome is 58 years; most patients are white women, and 80% have anti-Ro/SSA antibodies. It may occur after weeks to years of therapy.61 Chronic cutaneous lupus has been reported with fluorouracil and NSAIDs.60 It can take months for skin lesions to resolve after the offending drug has been stopped.10
A separate category of drug-induced lupus is that involving TNF-α inhibitors, such as adalimumab, etanercept, and infliximab. These are known to induce autoantibodies. Other theories explaining the mechanism for TNF-αinhibitor-induced lupus are that they cause a shift into other pathways of cytokine production or that they interfere with apoptosis.60 It is common for patients receiving these drugs to develop positive ANAs and anti-dsDNA. Antihistone antibodies are less commonly seen than with other drug-induced lupus (17% to 57%).62 As with traditional drug-induced lupus, the incidence of clinical lupus is low compared to the numbers that develop autoantibodies. Rashes, hypocomplementemia, leukopenia, and thrombocytopenia are more common features with TNF-α inhibitors than traditional drug-induced lupus, and arthralgias, arthritis, and myalgias are less common. The underlying diseases being treated with these drugs may be a factor in development of the observed reactions. Autoimmune diseases have also been reported following use of interferon therapy.60
The primary treatment for drug-induced lupus is stopping the implicated drug. Some patients require treatment with topical or systemic corticosteroids and supportive care, and a few may require immunosuppressive therapy.60,62
Immunizations
Patients with SLE are at increased risk for infections because of immune dysfunction caused by the disease itself and the immunosuppressive therapy the patients receive. It is important to try to protect patients against these infections, but there are areas of concern regarding the safety and efficacy of vaccines in patients with SLE. SLE cases developing or flaring after vaccine administration have been reported; the actual risk appears low when considering how many people receive immunizations. Another concern is that immunosuppressed patients may have an impaired response to vaccines as compared with healthy individuals. This can be assessed by checking titers after immunization. In some cases revaccination may be needed. Whenever possible, to achieve the best response, vaccines should be administered prior to initiating immunosuppressive medications. Killed vaccines are considered safe in immunosuppressed patients. It is recommended that SLE patients receive pneumococcal vaccine, since they are particularly susceptible to Streptococcus pneumoniae infections. They should also receive annual influenza vaccines, and, if considered to be at risk, hepatitis B vaccine. Live-attenuated virus vaccines, such as measles–mumps–rubella, varicella, zoster, intranasal influenza, and yellow fever, are contraindicated in patients receiving biologic agents.63 They should be avoided with consideration of risks versus benefits in patients taking high doses of other immunosuppressive drugs.64,65 Doses of corticosteroids equivalent to prednisone 20 mg/day or more given for at least 2 weeks are considered immunosuppressive.63 Live vaccines should be given at least 2 to 4 weeks before starting immunosuppressive drugs or 3 months after stopping them.63,66
PERSONALIZED PHARMACOTHERAPY
Pharmacotherapy is determined by disease manifestations and patient-specific factors. Hydroxychloroquine should be considered for all patients with SLE. Comorbidities and organ function should be considered in selection of therapy, as previously discussed.
Race appears to influence response to treatment, but many people are of mixed race. Genetic testing may provide a better guide in the future. In studies of lupus nephritis, whites with Western or Southern European backgrounds respond as well to low-dose IV cyclophosphamide (“Euro-Lupus” regimen of 500 mg every 2 weeks for six doses) as to high-dose regimens (500 to 1000 mg/m2 body surface area once a month for six doses) (Level B evidence). African Americans and Hispanics respond less well to IV cyclophosphamide than do whites or Asians. Patients of African or Hispanic origin may respond better to mycophenolate mofetil than to cyclophosphamide. Asians require lower doses of mycophenolate mofetil (Level C evidence).6 African Americans with lupus nephritis may respond to rituximab better than whites.42 Patients of African descent did not respond to belimumab in the BLISS studies.40
Blood concentrations of drugs are not usually measured in SLE management, even for drugs that are monitored that way when used for other diseases. Hydroxychloroquine blood concentrations appear to correlate with efficacy, but they are not routinely monitored.37 Although therapeutic mycophenolate drug concentration monitoring is used in transplant patients, it is not yet common practice in SLE patients. Preliminary studies have shown that MPA area under the plasma concentration–time curve appears to correlate with SLE disease activity but not adverse effects or daily doses.48 Patients should have TPMT testing before receiving azathioprine51 and be screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency before getting dapsone.21
Pregnancy plans should be considered in choosing therapy. Attention must be given to the effects of drugs on fertility and on the fetus, as well as the adverse effects of active disease on pregnancy outcomes.
EVALUATION OF THERAPEUTIC OUTCOMES
Patients must be assessed for the activity and extent of lupus and monitored for adverse drug effects. Monitoring for specific drugs is listed in Table 69-3. 
Many instruments have been developed and modified over the years to assess SLE therapy in trials. It is difficult to assess SLE therapy because milder forms of the disease may fluctuate, regardless of therapy. Examples of measures of disease activity include the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), and British Isles Lupus Assessment Group (BILAG). The SELENA-SLEDAI is a measure of disease activity that considers 24 manifestations. BILAG measures clinical disease activity in eight organ systems compared to the prior month, considering 86 disease manifestations. The organ domains are given scores based on severity: A (severe disease activity flare that requires additional treatment), B (moderate flare), C (mild, stable disease), D (previously affected but no current disease activity), and E (never been involved). Other instruments used in studies are the Systemic Lupus Activity Measure (SLAM) and European Consensus Lupus Activity Measurement (ECLAM).67 Individually, these indices were inadequate for showing superiority of new drugs over standard therapy. To overcome this problem, belimumab investigators developed the SRI assessment criteria. The SRI has three components: (a) Reduction in disease activity by SELENA-SLEDAI ≥4 points; (b) No worsening of disease activity (BILAG A) and no more than one new BILAG B score; and (c) <0.3 point increase (worsening) in physician global assessment (PGA). The PGA assesses patients’ general health status on a scale of 0 (no disease activity) to 3 (severe).40 Another important assessment of therapy is HRQoL, which may use a tool such as the generic Medical Outcomes Survey Short Form-36 (SF-36).67
A EULAR panel developed recommendations for the monitoring of patients with SLE in clinical practice and observational studies. Patients should be evaluated for SLE disease activity and organ involvement, cardiovascular risk factors, comorbidities, and risk for infection. Clinical and laboratory assessments should be performed every 6 to 12 months in patients with inactive disease and no organ damage, and more frequently if abnormalities are found.68
The Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) may be used to assess the extent and severity of cutaneous lupus erythematosus and response to therapy.69
ABBREVIATIONS
REFERENCES
1. Scofield RH, Oates J. The place of William Osler in the description of systemic lupus erythematosus. Am J Med Sci 2009;338:409–412.
2. D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007;369:587–596.
3. Pons-Estel GJ, Alarcón GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010;39:257–268.
4. Tsokos GC. Systemic lupus erythematosus. N Engl J Med 2011;365:2110–2121.
5. Sánchez E, Rasmussen A, Riba L, et al. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian–European populations. Arthritis Rheum 2012;64:3687–3694.
6. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012;64:797–808.
7. Robinson M, Cook SS, Currie LM. Systemic lupus erythematosus: A genetic review for advanced practice nurses. J Am Acad Nurse Pract 2011;23:629–637.
8. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358:929–939.
9. Lessard CJ, Adrianto I, Ice JA, et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet 2012;90:648–660.
10. Zandman-Goddard G, Solomon M, Rosman Z, et al. Environment and lupus-related diseases. Lupus 2012;21:241–250.
11. Sawalha AH, Harley JB, Scofield RH. Autoimmunity and Klinefelter’s syndrome: When men have two X chromosomes. J Autoimmun 2009;33:31–34.
12. Jacob N, Jacob CO. On anti-tumor necrosis factor-induced systemic lupus erythematosus. J Rheumatol 2010;37:3–5.
13. Choi ST, Kang JI, Park IH, et al. Subscale analysis of quality of life in patients with systemic lupus erythematosus: Association with depression, fatigue, disease activity and damage. Clin Exp Rheumatol 2012;30:665–672.
14. Tan TC, Fang H, Magder LS, Petri MA. Differences between male and female systemic lupus erythematosus in a multiethnic population. J Rheumatol 2012;39:759–769.
15. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–2686.
16. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–1277.
17. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
18. Ruperto N, Hanrahan LM, Alarcón GS, et al. International consensus for a definition of disease flare in lupus. Lupus 2011;20:453–462.
19. Santiago-Casas Y, Vilá LM, McGwin G Jr, et al. Association of discoid lupus erythematosus with clinical manifestations and damage accrual in a multiethnic lupus cohort. Arthritis Care Res (Hoboken) 2012;64:704–712.
20. Hansen CB, Dahle KW. Cutaneous lupus erythematosus. Dermatol Ther 2012;25:99–111.
21. Chang AY, Werth VP. Treatment of cutaneous lupus. Curr Rheumatol Rep 2011;13:300–307.
22. Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: Report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010;69:2074–2082.
23. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review. Ann Rheum Dis 2010;69:20–28.
24. Drug Therapeutics Bulletin. Systemic lupus erythematosus—An update. Drug Ther Bull 2011;49:81–84.
25. Mosca M, Tani C, Carli L, Bombardieri S. Glucocorticoids in systemic lupus erythematosus. Clin Exp Rheumatol 2011;29:S126–S129.
26. Haija AJ, Schulz SW. The role and effect of complementary and alternative medicine in systemic lupus erythematosus. Rheum Dis Clin North Am 2011;37:47–62.
27. Food and Drug Administration. HHS. Labeling and effectiveness testing; sunscreen drug products for over-the-counter human use. Final rule. Fed Regist 2011;76:35620–35665.
28. Ezra N, Jorizzo J. Hydroxychloroquine and smoking in patients with cutaneous lupus erythematosus. Clin Exp Dermatol 2012;37:327–334.
29. Turchin I, Bernatsky S, Clarke AE, et al. Cigarette smoking and cutaneous damage in systemic lupus erythematosus. J Rheumatol 2009;36:2691–2693.
30. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a Task Force at the 13th International Congress on Antiphospholipid Antibodies. Lupus 2011;20:206–218.
31. Artifoni M, Puechal X. How to treat refractory arthritis in lupus? Joint Bone Spine 2012;79:347–350.
32. Elbirt D, Sthoeger D, Asher I, Sthoeger ZM. The management of systemic lupus erythematosus: Facts and controversies. Clin Dermatol 2010;28:330–336.
33. Kamen DL. Vitamin D in lupus—New kid on the block? Bull NYU Hosp Jt Dis 2010;68:218–222.
34. Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011;13:77–80.
35. Pons-Estel GJ, Alarcón GS, González LA, et al. Possible protective effect of hydroxychloroquine on delaying the occurrence of integument damage in lupus: LXXI, data from a multiethnic cohort. Arthritis Care Res (Hoboken) 2010;62:393–400.
36. Alarcón GS, McGwin G, Bertoli AM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: Data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66:1168–1172.
37. Marmor MF, Kellner U, Lai TY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118:415–422.
38. Costedoat-Chalumeau N, Leroux G, Piette JC, Amoura Z. Why all systemic lupus erythematosus patients should be given hydroxychloroquine treatment? Joint Bone Spine 2010;77:4–5.
39. Dennis GJ. Belimumab: A BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. Clin Pharmacol Ther 2012;91:143–149.
40. Burness CB, McCormack PL. Belimumab: In systemic lupus erythematosus. Drugs 2011;71:2435–2444.
41. van Vollenhoven RF. Rituximab—Shadow, illusion or light? Autoimmun Rev 2012;11:563–567.
42. Coca A, Sanz I. Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumatol 2012;24:451–456.
43. Dall’Era M, Chakravarty EF. Treatment of mild, moderate, and severe lupus erythematosus: Focus on new therapies. Curr Rheumatol Rep 2011;13:308–316.
44. Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: Alternative definitions of complete response support conflicting conclusions. Arthritis Rheum 2012;64:3660–3665.
45. Aringer M, Smolen JS. TNF inhibition in SLE: Where do we stand? Lupus 2009;18:5–8.
46. Aringer M, Burkhardt H, Burmester GR, et al. Current state of evidence on ‘off-label’ therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland—A consensus report. Lupus 2012;21:386–401.
47. Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: A data-driven review. Arthritis Rheum 2010;62:9–21.
48. Dall’Era M. Mycophenolate mofetil in the treatment of systemic lupus erythematosus. Curr Opin Rheumatol 2011;23:454–458.
49. Dall’Era M, Stone D, Levesque V, et al. Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide. Arthritis Care Res (Hoboken) 2011;63:351–357.
50. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011;365:1886–1895.
51. Schmajuk G, Yazdany J. Drug monitoring in systemic lupus erythematosus: A systematic review. Semin Arthritis Rheum 2011;40:559–575.
52. Amital H, Szekanecz Z, Szucs G, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: Is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis 2010;69:1155–1157.
53. Birmingham DJ, Hebert LA, Song H, et al. Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans. Lupus 2012;21:855–864.
54. Ruiz-Irastorza G, Gordo S, Olivares N, et al. Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage. Arthritis Care Res (Hoboken) 2010;62:1160–1165.
55. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv 2011;66:639–653.
56. Clowse ME. Managing contraception and pregnancy in the rheumatologic diseases. Baillieres Best Pract Res Clin Rheumatol 2010;24:373–385.
57. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010;376:1498–1509.
58. Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64:2311–2318.
59. Wijetilleka S, Scoble T, Khamashta M. Novel insights into pathogenesis, diagnosis and treatment of antiphospholipid syndrome. Curr Opin Rheumatol 2012;24:473–481.
60. Chang C, Gershwin ME. Drug-induced lupus erythematosus: Incidence, management and prevention. Drug Saf 2011;34:357–374.
61. Lowe G, Henderson CL, Grau RH, et al. A systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011;164:465–472.
62. Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: Report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011;50:619–625.
63. Millet A, Decaux O, Perlat A, et al. Systemic lupus erythematosus and vaccination. Eur J Intern Med 2009;20:236–241.
64. Heijstek MW, Ott de Bruin LM, Bijl M, et al. EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. Ann Rheum Dis 2011;70:1704–1712.
65. Anonymous. Recommended adult immunization schedule—United States, 2012. JAMA 2012;308:22–28.
66. O’Neill SG, Isenberg DA. Immunizing patients with systemic lupus erythematosus: A review of effectiveness and safety. Lupus 2006;15:778–783.
67. Strand V, Chu AD. Measuring outcomes in systemic lupus erythematosus clinical trials. Expert Rev Pharmacoecon Outcomes Res 2011;11:455–468.
68. Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010;69:1269–1274.
69. Kuhn A, Meuth AM, Bein D, et al. Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI): A modified outcome instrument for cutaneous lupus erythematosus. Br J Dermatol 2010;163:83–92.