belimumb n les
TRANSCRIPT
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T h e n e w e n g l a n d j o u r n a l o f me dicine
n engl j med 368;16 nejm.org april 18, 20131528
ThisJournalfeature begins with a case vignette that includes a therapeutic recommendation. A discussionof 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 authors clinical recommendations.
Belimumab for Systemic Lupus
ErythematosusBevra Hannahs Hahn, M.D.
From the Department of Medicine, DavidGeffen School of Medicine, University ofCalifornia Los Angeles, Los Angeles. Ad-dress reprint requests to Dr. Hahn at theDepartment of Medicine, Division of Rheu-matology, David Geffen School of Medi-cine at the University of California LosAngeles, 1000 Veteran Ave., Los Angeles,CA 90095, or at [email protected].
N Engl J Med 2013;368:1528-35.
DOI: 10.1056/NEJMct1207259
Copyright 2013 Massachusetts Medical Society.
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 antidouble-
stranded DNA (dsDNA) antibodies. Treatment with analgesics and hydroxychloro-quine 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 hospi-
talizations 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 rheuma-
tologist recommended a trial of belimumab.
The Clinical Problem
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 background1; 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,1with 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 acceler-
ated atherosclerosis.2
Approximately 80% of patients with SLE have persistently active disease orfrequent flares.3In the United States, one third of patients with musculoskeletalmanifestations of lupus are unable to work.4 Among patients with proliferativeforms of lupus glomerulonephritis, the risk of end-stage renal disease is 10 to30%.5 In the majority of patients with SLE, irreversible organ damage developsover a period of 6 years or more,6often from both disease and treatments, withadverse effects of glucocorticoids being a major problem. Annual individual directcostsof SLE have been estimated at $13,735 to $20,926 in 2011 U.S. dollars.7
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PATHOPHYSIOLOGY A ND EFFECT S
OF THERAP Y
SLE is caused by pathogenic autoantibodies (which
appear a few years before the first clinical symp-
toms8) and immune complexes that bind to tis-
sue, fix complement, activate inflammatory re-
sponses, and mediate tissue damage. In peoplewho are genetically predisposed to autoimmuni-
ty and SLE,9,10 normal immune responses be-
come dysregulated, autoantibody production in-
creases and persists, and both the innate and
adaptive immune systems remain activated.11,12
Environmental triggers include EpsteinBarr vi-
rus infection13; exposure to ultraviolet light, es-
trogen-containing medications, and silica dust;
and smoking tobacco.14
B cells (Fig. 1) are central in the pathogenesisof SLE, because they are precursors for plasma
cells that secrete antibodies; they also presentantigens to T cells and other B cells, and theysecrete proinflammatory cytokines.15B cells areactivated by T cells. B cells and plasmacytoiddendritic cells can also be activated throughendosomal toll-like receptors, some of whichrecognize DNA- and RNA-containing proteins.16In patients with SLE, numbers of circulatingplasma cells, plasmablasts, and late transitionalB cells (a late stage of maturation in B cells) areincreased.17Higher-than-normal proportions ofB cells and T cells are activated,11,15and activa-tion pathways are abnormal,11,12 favoring auto-immunity and inflammation. Regulatory cellsof several types that suppress B cells and helperT cells are low in numbers or dysfunctional inmost patients with SLE.18
Increased B-cell activation is due in part toincreased levels of growth factors, includingB-lymphocyte stimulator (BLyS), also called B-cellactivating factor (BAFF).19BLyS is a growth fac-tor required for B-cell survival, maturation, andactivation; germinal-center formation; the devel-
opment of B cells into plasma cells; and immu-noglobulin production. Many of the subsets ofmaturing B cells are completely dependent onthe binding of BAFF receptors by BLyS to surviveand mature (Fig. 1). Mature, activated B cellsdifferentiate into plasmablasts or memory B cells;memory cells lack BAFF receptors. At least 50%of people with SLE have elevated plasma levels ofsoluble BLyS,20and there is a weak but signifi-
cant correlation between high levels and activedisease.
Belimumab is a fully humanized IgG1-monoclonal antibody that binds to soluble BLySand inhibits its binding to receptors and thus itsactivity (Fig. 1C).19 Administration of belimu-mab depletes activated and naive B cells as well
as plasma cells but not memory B cells.19,21Thepersistence of memory B cells in patients withSLE could be a limitation of belimumab therapy,because these cells can give rise to progeny thatcan secrete the entire undesirable autoantibodyrepertoire; it is also an advantage, because pro-tective antibodies against influenza, pneumo-coccus, and tetanus are maintained and can besuccessfully induced with revaccination.22
CLINICAL EVIDENCE
Two large, phase 3, multicenter, prospective, ran-domized, controlled trials have compared belim-
umab with placebo in patients with SLE who
were receiving standard therapies. The trials are
designated BLISS-5223and BLISS-7624according
to their duration in weeks. In both trials, partici-
pants were required to meet the American Col-
lege of Rheumatology criteria for the diagnosis
of SLE25(see the Supplementary Appendix, avail-
able 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 AsiaPacific 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 be-
limumab at a dose of 1 mg per kilogram of body
weight, belimumab at a dose of 10 mg per kilo-
gram, or placebo. The study drugs were adminis-
tered by intravenous infusion on days 0, 14, and 28,
then every 28 days. The primary outcome mea-
sure in both studies was the Systemic Lupus Ery-thematosus Responder Index (SRI)26at 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 showedsignificant improvement in the SRI with 10 mgof belimumab per kilogram as compared with
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placebo. Improvement in several outcomes oc-curred with belimumab at a dose of 1 mg perkilogram, but the dose of 10 mg per kilogramwas more reliably effective and is the dose ap-proved by the Food and Drug Administration(FDA); therefore, only the results for the 10-mg-per-kilogram dose are discussed here. In thecombined studies,23,24,27a response occurred in
50.6% of patients assigned to belimumab at adose of 10 mg per kilogram versus 38.6% ofpatients assigned to placebo (P
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BLISS-76 trial, differences in SRI results betweenbelimumab at a dose of 10 mg per kilogram andplacebo were no longer significant at 76 weeks.
CLINICAL 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. Be-
limumab is generally given to patients with pro-
files 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 glucocor-
ticoids required to alleviate discomfort and im-
prove functioning, despite concurrent treatment
with an antimalarial agent (chloroquine or hy-
droxychloroquine) plus glucocorticoids and one
additional immunosuppressant (mycophenolate
mofetil, azathioprine, or methotrexate).
Alternatives to belimumab are other agentsthat suppress SLE disease activity that persistsdespite the use of antimalarial agents and low-dose glucocorticoids. These include methotrex-ate, azathioprine, mycophenolate mofetil, cyclo-phosphamide, and possibly rituximab andcalcineurin inhibitors. All these alternatives arelimited by toxic effects and by a failure to con-trol disease in approximately one third of pa-tients. Thus, belimumab may address an unmetneed for some patients. However, it is importantto note that to date there are no data from trials
involving head-to-head comparisons of belim-umab with any of these other therapies.
Before belimumab therapy is initiated, theclinician should record the level of SLE diseaseactivity so that the response can be accuratelyevaluated, particularly because the responsetends to be slow. I use the Safety of Estrogensin Lupus Erythematosus National Assessment(SELENA) modification of the Systemic LupusErythematosus Disease Activity Index (SLEDAI)(the SELENASLEDAI scale).28-30 This scale isuseful because it is relatively simple; scoresrange from 0 to 105, with higher scores indicat-ing more severe disease activity (see the Supple-mentary Appendix). In the phase 3 trials, theaverage SELENASLEDAI score on enrollmentranged from 9 to 10. However, other measuresare available.30,31
Some health insurance plans require that allcandidates for belimumab have a positive ANAtest, a positive test for anti-dsDNA antibodies, orboth when treatment begins (as in the BLISS tri-als); seropositivity identifies those who are likely
to have a response. Measurement of serumcomplement is also useful, because low levelsidentify patients who are likely to have a re-sponse. Contraindications to belimumab thera-py include active or chronic infections. I recom-mend that candidates be screened for humanimmunodeficiency virus infection, hepatitis Band C, tuberculosis, cytomegalovirus infection (ifthe patient is taking immunosuppressive agents),and any other suspected active or chronic in-fection.
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 withSLE treated with belimumab (Panel C). The serum con-
centration of soluble B-lymphocyte stimulator (BLyS),also called B-cell activating factor (BAFF), is increased
in many patients with SLE. BAFF receptors (BAFF-Rs;cells highly dependent on BAFF to survive have red re-
ceptors; those that use BAFF to increase maturation or
function are shown in orange) bind BLyS and one otherB-cell growth factor. BAFF-Rs are present on the surface
of some B cells, some helper T cells, and dendritic cells.Cells with BAFF receptors shown in red are highly de-
pendent on BLyS for survival and maturation; cells withBAFF receptors shown in orange are less dependent on
BLyS for survival. Cells that are dependent on BLyS forsurvival are in the B-lymphocyte series, shown maturing
from the top of the figure downward. Immature B cellsare released from bone marrow into the circulation and
mature through transitional stages into naive B cells.
The naive B cells enter lymphoid tissue in marginal zones(without T-cell stimulation), germinal centers (usually ex-
posed to T-cell stimulation), or follicular zones (usuallyexposed to T-cell stimulation). The naive cells mature
to activated B cells, which mature to immunoglobulin-secreting plasma cells or memory B cells. Plasma cells
secrete IgM or IgG, including autoantibodies. In general,pathogenic subgroups of autoantibodies and immune
complexes contain IgG, which is dependent on helperT cells. Both helper T cells and activated B cells are sup-
pressed by regulatory mechanisms, including regulator yT cells (Treg); these regulatory cells are decreased or dys-
functional during active SLE. Plasmacytoid dendritic cells
are a major source of interferon-, the levels of whichare often elevated in SLE; they can drive B cells to secrete
IgM autoantibodies in the absence of helper T cells.Myeloid dendritic cells present antigen to T cells and
drive T-cell help. Monocyte-derived macrophages clearimmune complexes and apoptotic cells (which are a source
of autoantigens such as nucleosomes for antibodies toDNA and Ro for antibodies to Ro). The clearance capac-
ity of these cells is impaired in people with active SLE.
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Belimumab is given intravenously at a dose of10 mg per kilogram on days 0, 14, and 28 andthen every 28 days. The infusions, especially thefirst two, should be administered at an infusioncenter, because reactions to the first two infu-sions are not unusual.32-34Preinfusion treatment
with acetaminophen, diphenhydramine, intra-venous glucocorticoids, or a combination of theseagents can be used to mitigate such reactions.Belimumab has no known drug interactions, andno dose adjustments are required for renal orhepatic dysfunction. Patients should plan tospend approximately a half day each month at theinfusion center. They should also be informedabout possible adverse effects, including infusionreactions, allergic responses, headache, upper re-spiratory symptoms, an increase in arthralgias
and diffuse aching, and an increased risk of seri-ous infections (discussed below).
The clinician should consider scheduling out-patient visits at intervals of 4 to 8 weeks (ormore frequently) to assess the response to treat-ment, as indicated by the level of disease activity,
extent of physical functioning, and glucocorti-coid requirement, and to check for any adverseeffects of belimumab. The treatment responsecan be assessed on the basis of the patients re-port or the physicians evaluation. It is also mypractice to measure anti-dsDNA and complementlevels at 8-week intervals: falling anti-dsDNAtiters and rising serum complement levels sug-gest an increased likelihood of a good responseto belimumab27,35-37and other medications usedto treat SLE.
Table 1.Outcomes at 52 Weeks in Phase 3 Trials of Belimumab.*
Trial Placebo Belimumab P Value
Response to study medication (% of patients)
BLISS-52 44 58
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During the first 6 months of belimumabtherapy, I have observed a response to treatmentin approximately one third of patients, adverseeffects leading to discontinuation of treatmentin another third, and neither a response noradverse effects in the remaining third. Amongpatients who had a response, flares were less
frequent and less severe, improvement occurredin arthritis and dermatitis (including alopecia),and the glucocorticoid dose was reduced suc-cessfully, although not to zero. If there is noindication of clinical or laboratory improvementat 6 months, I discontinue belimumab and selecta different immunosuppressive regimen. To date,there is no information regarding adjustment ofthe dose or the frequency of administration toincrease the likelihood of a response or to de-crease the risk of adverse effects.
In my experience, discontinuation of belimu-
mab therapy in patients who have had a responseis followed by disease flares in some patientsbut a sustained response in others. A study in-volving patients who had a response and contin-ued treatment every 28 days for up to 4 yearsshowed that improvement was maintained in90% of patients.35
Belimumab treatment is expensive. At mycenter, the cost is approximately $2,000 for eachintravenous treatment (i.e., for the drug and itsadministration); with three infusions during thefirst 28 days and one infusion per month there-after, the total cost for the first year of treatmentis $28,000. Approximate annual prices in U.S.dollars of generic prescription drugs at theusual doses for patients with systemic lupus ery-thematosus in Los Angeles are as follows: pred-nisone, $140; hydroxychloroquine, $132; oralmethotrexate, $432; azathioprine, $468; andmycophenolate mofetil, $1,224.
ADVERSE EFFECTS
Patients with SLE who are receiving immunosup-pressive therapies are at increased risk for infec-
tion, certain types of tumors, and death or dis-
ability related to SLE.2,35These risks do not appear
to be significantly increased by the use of be-
limumab. In the studies of belimumab that last-
ed 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.23,24,32,35Total
adverse events were similar in all treatment
groups.23,24,32,35 In the BLISS trials,23,24serious
or severe adverse events occurred in 13 to 20% of
patients and were similar in all groups.
Infusion reactions (starting on the day of infu-sion) in the longer trial, BLISS-76, were morecommon in the patients assigned to belimumabat a dose of 10 mg per kilogram than in patients
assigned to placebo (13.6% vs. 9.8%). The reac-tions were serious or severe in 1.1% of patientsassigned to belimumab at a dose of 10 mg perkilogram. In the 4-year follow-up study, infusionreactions declined, as did rates of serious infec-tions, but they did not reach zero.35In 2012, themanufacturer of belimumab, GlaxoSmithKline,released a letter warning physicians that severeinfusion and hypersensitivity reactions may oc-cur; one death from hypotension and angioedemaafter infusion had been recorded.33Infusion re-actions tend to begin a few hours after the in-
fusion; they occur less frequently after the firsttwo infusions.32Premedication (e.g., with diphen-hydramine or intravenous glucocorticoids)32-34hasbeen reported to mitigate the severity of infu-sion reactions.
Rates of infection, including serious infec-tions requiring intravenous antibiotics or hos-pitalization, were not significantly higher withbelimumab than with placebo in either of thephase 3 trials (severe infections occurred in 7 to8% of patients assigned to belimumab and in 6%of patients assigned to placebo), and my experi-ence has been consistent with this observation.Compelling suicidal thoughts developed in twoof my patients, who discontinued the medica-tion; this possible adverse effect was reported inthe BLISS-52 trial.23Other reactions that I haveseen are the same as those reported in the phase3 trials; they include headache, low-grade fever,temporary worsening of arthralgias, fatigue, andnausea all of which are usually short-lived.23,24,32,34
Area s of Uncertainty
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 gen-
eral use. The FDA approval specifies that this
agent is indicated for patients with active, auto-
antibody-positive SLE who are receiving standard
therapy, including glucocorticoids, antimalarial
agents, immunosuppressive agents, and nonste-
roidal antiinflammatory drugs. This suggests
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that other immunosuppressive agents should be
tried first, as in the phase 3 trials. One important
question is whether belimumab would be effec-
tive and well tolerated as the first immunosup-
pressive agent in patients with SLE to be add-
ed when antimalarial agents alone or combined
with low-dose glucocorticoids are not enough.
A second question is how belimumab can bestbe used in combination therapy. It is not known,for example, whether belimumab plus an anti-malarial agent is better or worse than belim-umab plus an immunosuppressive agent such asmycophenolate mofetil, azathioprine, or metho-trexate. Another possibility would be to combinebelimumab with rituximab. This combination hasthe theoretical advantage that rituximab could beadministered to deplete peripheral-blood B cells,followed by the administration of belimumab toprevent 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 eithercentral nervous system disease or active lupusnephritis is also unknown. Such patients wereexcluded from the phase 3 trials. However, inthose trials, 267 patients had renal involvement;among these patients, belimumab, as comparedwith placebo, was associated with significant im-provements in proteinuria27,37and in the SLEDAImeasurements of lupus nephritis, and therewere other trends favoring belimumab, particu-larly among patients who also received myco-phenolate.37
One final consideration concerns the longer-term care of patients treated with belimumab.Are there unanticipated adverse effects of belim-umab when it is used for several years? Will in-activating antibodies against belimumab causethe efficacy of the drug to decline over time, aswith infliximab, or might immune complexescause disease? The best way to discontinue be-limumab in patients who have a response and
the likelihood of maintaining improvement aftersuch discontinuation have also not been estab-lished.
Guidelines
Because belimumab is a new therapeutic agent,
there are no current guidelines in Englishfrom
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 ap-
proval statement.
Conclusions
In the patient described in the vignette, the clini-cal activity of SLE declined after 16 weeks of be-limumab treatment. Her arthritis and fatiguewere substantially improved, and her flares weremilder and less frequent. Her prednisone dosewas tapered from 30 mg to 15 mg a day over aperiod of 24 weeks. However, when the predni-sone dose was reduced further, to 12.5 mg daily,she had a flare of SLE and again required 30 mgof prednisone per day. Disappointed, she electedto discontinue belimumab.
This patients case illustrates several prob-
lems associated with the use of a new treatmentin patients with a chronic disease. If the use ofthe treatment is inconvenient (as in the case ofbelimumab, which requires intravenous admin-istration), many physicians reserve it for patientswho have not had an adequate response to sev-eral standard treatments. Thus, the new treat-ment is used in people who are unlikely to have aresponse, often leading to the erroneous conclu-sion that it is not very effective. In the case ofthis patient, at the initiation of belimumab treat-ment, she had a positive ANA assay and moder-ately high level of disease activity (her SELENASLEDAI score was 6). However, she did not haveanti-dsDNA antibodies or hypocomplementemia.Thus, the likelihood of a response was not asgood as in a person with a SELENASLEDAIscore of 10 or higher, high anti-dsDNA antibodytiters, and low complement levels. In addition,many patients expect a dramatic response froma new treatment and may not appreciate incre-mental improvements. Presumably, belimumabwill find its place in the therapeutic armamen-
tarium with more clinical experience, and bothpatients and physicians will have a clearer under-standing of what to expect from this new agent.
Dr. Hahn reports receiving consulting fees through her in-stitution from UCB, Abbott Laboratories, and Eli Lilly; grantsupport through her institution from Aspreva Pharmaceuticalsand Teva Pharmaceuticals; and fees for serving on a data andsafety monitoring board from Anthera Pharmaceuticals. Noother potential conflict of interest relevant to this article wasreported.
Disclosure forms provided by the author are available withthe ful l text of this a rticle at NEJM.org.
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