Belimumab for Systemic Lupus Erythematosus

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e clinical therapeutics Belimumab for Systemic Lupus Erythematosus Bevra Hannahs Hahn, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author s clinical recommendations. A 20-year-old woman was evaluated by her rheumatologist because she was disabled by flares of systemic lupus erythematosus (SLE). A diagnosis of SLE had been made 2 years earlier, on the basis of a photosensitive malar rash, oral ulcers, polyarthritis, pericarditis, and positive assays for antinuclear antibodies (ANA) and anti doublestranded DNA (dsdna) antibodies. Treatment with analgesics and hydroxychloroquine for 6 months was not beneficial; prednisone at a dose of 40 mg daily resulted in some improvement, but the patient gained 6.8 kg (15 lb) and required two hospitalizations for infections. SLE flares occurred when the prednisone dose was less than 30 mg daily. Trials of methotrexate, mycophenolate mofetil, and azathioprine either had unacceptable side effects or failed to control flares or permit prednisone tapering. On examination, she had cushingoid features with 20 swollen, tender joints and 3 oral ulcers. The ANA titer was positive, at 1:320. An assay for anti-dsdna antibodies was negative, and the serum complement level was normal. The rheumatologist recommended a trial of belimumab. The Clinic a l Problem From the Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles. Address reprint requests to Dr. Hahn at the Department of Medicine, Division of Rheumatology, David Geffen School of Medicine at the University of California Los Angeles, 1000 Veteran Ave., Los Angeles, CA 90095, or at bhahn@mednet.ucla.edu. N Engl J Med 2013;368: DOI: /NEJMct Copyright 2013 Massachusetts Medical Society. SLE is a chronic autoimmune disease with no currently known cure. An estimated 70 to 90% of affected persons are women, with an onset usually in the childbearing years. The prevalence is 20 to 70 cases per 100,000 women and varies according to race and ethnic background 1 ; the higher prevalence rates are among Latinos, blacks, and Afro-Caribbeans, and the lower prevalence rates are among whites and Asians. Overall survival rates also vary by race and ethnic background, 1 with a 5-year survival rate of approximately 95% among whites, 90% among blacks, and 87% among Hispanics. Men, persons in lower socioeconomic groups, and patients with nephritis have lower survival rates than other patients with SLE. Leading causes of death are active disease (particularly nephritis), infections, and accelerated atherosclerosis. 2 Approximately 80% of patients with SLE have persistently active disease or frequent flares. 3 In the United States, one third of patients with musculoskeletal manifestations of lupus are unable to work. 4 Among patients with proliferative forms of lupus glomerulonephritis, the risk of end-stage renal disease is 10 to 30%. 5 In the majority of patients with SLE, irreversible organ damage develops over a period of 6 years or more, 6 often from both disease and treatments, with adverse effects of glucocorticoids being a major problem. Annual individual direct costs of SLE have been estimated at $13,735 to $20,926 in 2011 U.S. dollars n engl j med 368;16 nejm.org april 18, 2013

2 clinical Therapeutics PATHOPH YSIOL O GY A ND EFFEC T S OF THER A PY SLE is caused by pathogenic autoantibodies (which appear a few years before the first clinical symptoms 8 ) and immune complexes that bind to tissue, fix complement, activate inflammatory responses, and mediate tissue damage. In people who are genetically predisposed to autoimmunity and SLE, 9,10 normal immune responses become dysregulated, autoantibody production increases and persists, and both the innate and adaptive immune systems remain activated. 11,12 Environmental triggers include Epstein Barr virus infection 13 ; exposure to ultraviolet light, estrogen-containing medications, and silica dust; and smoking tobacco. 14 s (Fig. 1) are central in the pathogenesis of SLE, because they are precursors for plasma s that secrete antibodies; they also present antigens to T s and other s, and they secrete proinflammatory cytokines. 15 s are activated by T s. s and plasmacytoid dendritic s can also be activated through endosomal toll-like receptors, some of which recognize DNA- and RNA-containing proteins. 16 In patients with SLE, numbers of circulating plasma s, plasmablasts, and late transitional s (a late stage of maturation in s) are increased. 17 Higher-than-normal proportions of s and T s are activated, 11,15 and activation pathways are abnormal, 11,12 favoring autoimmunity and inflammation. Regulatory s of several types that suppress s and helper T s are low in numbers or dysfunctional in most patients with SLE. 18 Increased B- activation is due in part to increased levels of growth factors, including B-lymphocyte stimulator (BLyS), also called B- activating factor (BAFF). 19 BLyS is a growth factor required for B- survival, maturation, and activation; germinal-center formation; the development of s into plasma s; and immunoglobulin production. Many of the subsets of maturing s are completely dependent on the binding of BAFF receptors by BLyS to survive and mature (Fig. 1). Mature, activated s differentiate into plasmablasts or memory s; memory s lack BAFF receptors. At least 50% of people with SLE have elevated plasma levels of soluble BLyS, 20 and there is a weak but significant correlation between high levels and active disease. Belimumab is a fully humanized IgG1-λ monoclonal antibody that binds to soluble BLyS and inhibits its binding to receptors and thus its activity (Fig. 1C). 19 Administration of belimumab depletes activated and naive s as well as plasma s but not memory s. 19,21 The persistence of memory s in patients with SLE could be a limitation of belimumab therapy, because these s can give rise to progeny that can secrete the entire undesirable autoantibody repertoire; it is also an advantage, because protective antibodies against influenza, pneumococcus, and tetanus are maintained and can be successfully induced with revaccination. 22 CLINIC A L E V IDENCE Two large, phase 3, multicenter, prospective, randomized, controlled trials have compared belimumab with placebo in patients with SLE who were receiving standard therapies. The trials are designated BLISS and BLISS according to their duration in weeks. In both trials, participants were required to meet the American College of Rheumatology criteria for the diagnosis of SLE 25 (see the Supplementary Appendix, available with the full text of this article at NEJM.org), to have active disease, and to be seropositive (ANA titer 1:80 or anti-dsdna antibody titer 30 IU per milliliter) at screening. The BLISS-52 trial involved 865 patients from Latin America, the Asia Pacific region, and eastern Europe. The BLISS-76 trial involved 819 patients from North America, Central America, and Europe. In both studies, patients were randomly assigned to belim umab at a dose of 1 mg per kilogram of body weight, belimumab at a dose of 10 mg per kilogram, or placebo. The study drugs were administered by intravenous infusion on days 0, 14, and 28, then every 28 days. The primary outcome measure in both studies was the Systemic Lupus Erythematosus Responder Index (SRI) 26 at week 52. The SRI is a combination of measures used to evaluate disease activity; results are reported as the percentage of patients who meet these criteria for clinical improvement. As shown in Table 1, both studies showed significant improvement in the SRI with 10 mg of belimumab per kilogram as compared with n engl j med 368;16 nejm.org april 18,

3 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A Healthy B Untreated SLE C SLE Response to Belimumab Low autoantibody levels Low immune complex levels Normal complement levels High levels of autoantibodies with some fixed to tissue High immune complex levels Low complement levels Lower autoantibody levels Lower immune complex levels Higher complement levels Normal BLyS level Increased BLyS level Inhibited BLyS Belimumab Monocytes and macrophages phagocytosis of immune complexes and apoptotic s BAFF-R s highly dependent on BLyS BAFF-R BAFF-R s not highly dependent on BLyS Immature bone marrow Transitional Immature bone marrow monocytes and macrophages defective phagocytosis of immune complexes and apoptotic s helper T Increased transitional s dendritic Monocytes and macrophages phagocytosis of immune complexes and apoptotic s Dendritic Immature bone marrow Transitional Dendritic naive and marginal-zone s Treg Helper T Naive germinal-center, follicular, and naive s Treg germinal-center, follicular, and naive s Naive marginal-zone and naive s germinal-center, follicular, and naive s Helper T marginal-zone s Treg Naive germinal-center and follicular s Memory Increased memory s Memory Memory Increased plasma s Increased plasma s IgM IgG IgG IgG IgM IgM IgG placebo. Improvement in several outcomes occurred with belimumab at a dose of 1 mg per kilogram, but the dose of 10 mg per kilogram was more reliably effective and is the dose approved by the Food and Drug Administration (FDA); therefore, only the results for the 10-mgper-kilogram dose are discussed here. In the combined studies, 23,24,27 a response occurred in 50.6% of patients assigned to belimumab at a dose of 10 mg per kilogram versus 38.6% of patients assigned to placebo (P<0.001). Improvement was seen in several secondary outcome measures as well (Table 1). The benefit of the 10-mg-per-kilogram dose of belimumab over placebo became apparent at 16 to 24 weeks; the benefit persisted through 52 weeks. 23,24 In the 1530 n engl j med 368;16 nejm.org april 18, 2013

4 clinical Therapeutics Figure 1. Effects of Belimumab on Biomarkers of Systemic Lupus Erythematosus (SLE) and on the Immune System. Shown is the immune system in the healthy state (Panel A), in a patient with SLE (Panel B), and in a patient with SLE treated with belimumab (Panel C). The serum concentration of soluble B-lymphocyte stimulator (BLyS), also called B- activating factor (BAFF), is increased in many patients with SLE. BAFF receptors (BAFF-Rs; s highly dependent on BAFF to survive have red receptors; those that use BAFF to increase maturation or function are shown in orange) bind BLyS and one other B- growth factor. BAFF-Rs are present on the surface of some s, some helper T s, and dendritic s. Cells with BAFF receptors shown in red are highly dependent on BLyS for survival and maturation; s with BAFF receptors shown in orange are less dependent on BLyS for survival. Cells that are dependent on BLyS for survival are in the B-lymphocyte series, shown maturing from the top of the figure downward. Immature s are released from bone marrow into the circulation and mature through transitional stages into naive s. The naive s enter lymphoid tissue in marginal zones (without T- stimulation), germinal centers (usually exposed to T- stimulation), or follicular zones (usually exposed to T- stimulation). The naive s mature to activated s, which mature to immunoglobulinsecreting plasma s or memory s. s secrete IgM or IgG, including autoantibodies. In general, pathogenic subgroups of autoantibodies and immune complexes contain IgG, which is dependent on helper T s. Both helper T s and activated s are suppressed by regulatory mechanisms, including regulatory T s (Treg); these regulatory s are decreased or dysfunctional during active SLE. cytoid dendritic s are a major source of interferon-α, the levels of which are often elevated in SLE; they can drive s to secrete IgM autoantibodies in the absence of helper T s. Myeloid dendritic s present antigen to T s and drive T- help. Monocyte-derived macrophages clear immune complexes and apoptotic s (which are a source of autoantigens such as nucleosomes for antibodies to DNA and Ro for antibodies to Ro). The clearance capacity of these s is impaired in people with active SLE. BLISS-76 trial, differences in SRI results between belimumab at a dose of 10 mg per kilogram and placebo were no longer significant at 76 weeks. CLINIC A L USE The indication for use of belimumab is a lack of clinical improvement despite standard treatment for active disease in seropositive patients with SLE. Determining what constitutes standard treatment is a matter of clinical judgment. Belimumab is generally given to patients with profiles similar to those in the phase 3 clinical trials that is, persons with clinical disease activity that interferes with the quality of life or with unacceptable side effects of the dose of glucocorticoids required to alleviate discomfort and improve functioning, despite concurrent treatment with an antimalarial agent (chloroquine or hydroxychloroquine) plus glucocorticoids and one additional immunosuppressant (mycophenolate mofetil, azathioprine, or methotrexate). Alternatives to belimumab are other agents that suppress SLE disease activity that persists despite the use of antimalarial agents and lowdose glucocorticoids. These include methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, and possibly rituximab and calcineurin inhibitors. All these alternatives are limited by toxic effects and by a failure to control disease in approximately one third of patients. Thus, belimumab may address an unmet need for some patients. However, it is important to note that to date there are no data from trials involving head-to-head comparisons of belimumab with any of these other therapies. Before belimumab therapy is initiated, the clinician should record the level of SLE disease activity so that the response can be accurately evaluated, particularly because the response tends to be slow. I use the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) modification of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (the SELENA SLEDAI scale) This scale is useful because it is relatively simple; scores range from 0 to 105, with higher scores indicating more severe disease activity (see the Supplementary Appendix). In the phase 3 trials, the average SELENA SLEDAI score on enrollment ranged from 9 to 10. However, other measures are available. 30,31 Some health insurance plans require that all candidates for belimumab have a positive ANA test, a positive test for anti-dsdna antibodies, or both when treatment begins (as in the BLISS trials); seropositivity identifies those who are likely to have a response. Measurement of serum complement is also useful, because low levels identify patients who are likely to have a response. Contraindications to belimumab therapy include active or chronic infections. I recommend that candidates be screened for human immunodeficiency virus infection, hepatitis B and C, tuberculosis, cytomegalovirus infection (if the patient is taking immunosuppressive agents), and any other suspected active or chronic infection. n engl j med 368;16 nejm.org april 18,

5 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 1. Outcomes at 52 Weeks in Phase 3 Trials of Belimumab.* Trial Placebo Belimumab P Value Response to study medication (% of patients) BLISS <0.001 BLISS Combined trials <0.001 Severe flare (% of patients) BLISS BLISS NS Prednisone dose reduced to 7.5 mg/day (% of patients) BLISS BLISS NS Normalized C3 level (% of patients) BLISS <0.001 BLISS Change from positive to negative anti-dsdna antibody assay (% of patients) BLISS <0.001 BLISS NS Normalized immunoglobulin levels (% of patients) BLISS <0.001 Mean increase in SF-36 score BLISS BLISS * The BLISS-52 trial 23 involved 865 patients, the BLISS-76 trial 24 involved 819 patients, and the combined trials 27 involved 1684 patients. Data are shown for patients who received the assigned study medication. The term dsdna denotes double-stranded DNA, and NS not significant. Data shown are for belimumab at a dose of 10 mg per kilogram of body weight. A response to the study medication was assessed with the use of the Systemic Lupus Erythematosus Responder Index (see Supplementary Appendix). 26 Results are for 76 weeks. Scores on the 36-Item Short-Form Health Survey (SF-36) range from 0 to 100, with higher scores indicating better healthrelated quality of life. Belimumab is given intravenously at a dose of 10 mg per kilogram on days 0, 14, and 28 and then every 28 days. The infusions, especially the first two, should be administered at an infusion center, because reactions to the first two infusions are not unusual Preinfusion treatment with acetaminophen, diphenhydra mine, intravenous glucocorticoids, or a combination of these agents can be used to mitigate such reactions. Belimumab has no known drug interactions, and no dose adjustments are required for renal or hepatic dysfunction. Patients should plan to spend approximately a half day each month at the infusion center. They should also be informed about possible adverse effects, including infusion reactions, allergic responses, headache, upper respiratory symptoms, an increase in arthralgias and diffuse aching, and an increased risk of serious infections (discussed below). The clinician should consider scheduling outpatient visits at intervals of 4 to 8 weeks (or more frequently) to assess the response to treatment, as indicated by the level of disease activity, extent of physical functioning, and glucocorticoid requirement, and to check for any adverse effects of belimumab. The treatment response can be assessed on the basis of the patient s report or the physician s evaluation. It is also my practice to measure anti-dsdna and complement levels at 8-week intervals: falling anti-dsdna titers and rising serum complement levels suggest an increased likelihood of a good response to belimumab 27,35-37 and other medications used to treat SLE n engl j med 368;16 nejm.org april 18, 2013

6 clinical Therapeutics During the first 6 months of belimumab therapy, I have observed a response to treatment in approximately one third of patients, adverse effects leading to discontinuation of treatment in another third, and neither a response nor adverse effects in the remaining third. Among patients who had a response, flares were less frequent and less severe, improvement occurred in arthritis and dermatitis (including alopecia), and the glucocorticoid dose was reduced successfully, although not to zero. If there is no indication of clinical or laboratory improvement at 6 months, I discontinue belimumab and select a different immunosuppressive regimen. To date, there is no information regarding adjustment of the dose or the frequency of administration to increase the likelihood of a response or to decrease the risk of adverse effects. In my experience, discontinuation of belimumab therapy in patients who have had a response is followed by disease flares in some patients but a sustained response in others. A study involving patients who had a response and continued treatment every 28 days for up to 4 years showed that improvement was maintained in 90% of patients. 35 Belimumab treatment is expensive. At my center, the cost is approximately $2,000 for each intravenous treatment (i.e., for the drug and its administration); with three infusions during the first 28 days and one infusion per month thereafter, the total cost for the first year of treatment is $28,000. Approximate annual prices in U.S. dollars of generic prescription drugs at the usual doses for patients with systemic lupus erythematosus in Los Angeles are as follows: prednisone, $140; hydroxychloroquine, $132; oral methotrexate, $432; azathioprine, $468; and mycophenolate mofetil, $1,224. A DV ER SE EFFEC T S Patients with SLE who are receiving immunosuppressive therapies are at increased risk for infection, certain types of tumors, and death or disability related to SLE. 2,35 These risks do not appear to be significantly increased by the use of belimumab. In the studies of belimumab that lasted 52 weeks to 4 years, deaths occurred in all groups, including the placebo groups; the death rate did not exceed that expected in the overall population of patients with SLE. 23,24,32,35 Total adverse events were similar in all treatment groups. 23,24,32,35 In the BLISS trials, 23,24 serious or severe adverse events occurred in 13 to 20% of patients and were similar in all groups. Infusion reactions (starting on the day of infusion) in the longer trial, BLISS-76, were more common in the patients assigned to belimumab at a dose of 10 mg per kilogram than in patients assigned to placebo (13.6% vs. 9.8%). The reactions were serious or severe in 1.1% of patients assigned to belimumab at a dose of 10 mg per kilogram. In the 4-year follow-up study, infusion reactions declined, as did rates of serious infections, but they did not reach zero. 35 In 2012, the manufacturer of belimumab, GlaxoSmithKline, released a letter warning physicians that severe infusion and hypersensitivity reactions may occur; one death from hypotension and angioedema after infusion had been recorded. 33 Infusion reactions tend to begin a few hours after the infusion; they occur less frequently after the first two infusions. 32 Premedication (e.g., with diphenhydramine or intravenous glucocorticoids) has been reported to mitigate the severity of infusion reactions. Rates of infection, including serious infections requiring intravenous antibiotics or hospitalization, were not significantly higher with belimumab than with placebo in either of the phase 3 trials (severe infections occurred in 7 to 8% of patients assigned to belimumab and in 6% of patients assigned to placebo), and my experience has been consistent with this observation. Compelling suicidal thoughts developed in two of my patients, who discontinued the medication; this possible adverse effect was reported in the BLISS-52 trial. 23 Other reactions that I have seen are the same as those reported in the phase 3 trials; they include headache, low-grade fever, temporary worsening of arthralgias, fatigue, and nausea all of which are usually shortlived. 23,24,32,34 A r e a s of Uncerta in t y Belimumab was approved by the FDA in 2011 for use in patients with active SLE. Thus, we have only 2 years of experience with the drug in general use. The FDA approval specifies that this agent is indicated for patients with active, autoantibody-positive SLE who are receiving standard therapy, including glucocorticoids, anti malarial agents, immunosuppressive agents, and nonsteroidal antiinflammatory drugs. This suggests n engl j med 368;16 nejm.org april 18,

7 T h e n e w e ngl a nd j o u r na l o f m e dic i n e that other immunosuppressive agents should be tried first, as in the phase 3 trials. One important question is whether belimumab would be effective and well tolerated as the first immunosuppressive agent in patients with SLE to be added when antimalarial agents alone or combined with low-dose glucocorticoids are not enough. A second question is how belimumab can best be used in combination therapy. It is not known, for example, whether belimumab plus an antimalarial agent is better or worse than belimumab plus an immunosuppressive agent such as mycophenolate mofetil, azathioprine, or methotrexate. Another possibility would be to combine belimumab with rituximab. This combination has the theoretical advantage that rituximab could be administered to deplete peripheral-blood s, followed by the administration of belimumab to prevent the elevations in BLyS levels that occur after use of rituximab. Whether belimumab can be used in patients with SLE that is mainly manifested as either central nervous system disease or active lupus nephritis is also unknown. Such patients were excluded from the phase 3 trials. However, in those trials, 267 patients had renal involvement; among these patients, belimumab, as compared with placebo, was associated with significant improvements in proteinuria 27,37 and in the SLEDAI measurements of lupus nephritis, and there were other trends favoring belimumab, particularly among patients who also received mycophenolate. 37 One final consideration concerns the longerterm care of patients treated with belimumab. Are there unanticipated adverse effects of belimumab when it is used for several years? Will inactivating antibodies against belimumab cause the efficacy of the drug to decline over time, as with infliximab, or might immune complexes cause disease? The best way to discontinue belimumab in patients who have a response and the likelihood of maintaining improvement after such discontinuation have also not been established. Guidelines Because belimumab is a new therapeutic agent, there are no current guidelines in English from the American College of Rheumatology or the European League against Rheumatism that give any specifics about its use in patients with SLE. Current practice is therefore based primarily on the approach taken in the phase 3 trials and, in the United States, on the terms of the FDA approval statement. C onclusions In the patient described in the vignette, the clinical activity of SLE declined after 16 weeks of belimumab treatment. Her arthritis and fatigue were substantially improved, and her flares were milder and less frequent. Her prednisone dose was tapered from 30 mg to 15 mg a day over a period of 24 weeks. However, when the prednisone dose was reduced further, to 12.5 mg daily, she had a flare of SLE and again required 30 mg of prednisone per day. Disappointed, she elected to discontinue belimumab. This patient s case illustrates several problems associated with the use of a new treatment in patients with a chronic disease. If the use of the treatment is inconvenient (as in the case of belimumab, which requires intravenous administration), many physicians reserve it for patients who have not had an adequate response to several standard treatments. Thus, the new treatment is used in people who are unlikely to have a response, often leading to the erroneous conclusion that it is not very effective. In the case of this patient, at the initiation of belimumab treatment, she had a positive ANA assay and moderately high level of disease activity (her SELENA SLEDAI score was 6). However, she did not have anti-dsdna antibodies or hypocomplementemia. Thus, the likelihood of a response was not as good as in a person with a SELENA SLEDAI score of 10 or higher, high anti-dsdna antibody titers, and low complement levels. In addition, many patients expect a dramatic response from a new treatment and may not appreciate incremental improvements. Presumably, belimumab will find its place in the therapeutic armamentarium with more clinical experience, and both patients and physicians will have a clearer understanding of what to expect from this new agent. Dr. Hahn reports receiving consulting fees through her institution from UCB, Abbott Laboratories, and Eli Lilly; grant support through her institution from Aspreva Pharmaceuticals and Teva Pharmaceuticals; and fees for serving on a data and safety monitoring board from Anthera Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org n engl j med 368;16 nejm.org april 18, 2013

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