Clinical UM Guideline


Subject: Belimumab (Benlysta®)
Guideline #: CG-DRUG-84 Publish Date:    02/27/2019
Status: Reviewed Last Review Date:    01/24/2019


This document addresses the use of belimumab (Benlysta, Human Genome Sciences (HGS) and GlaxoSmithKline, Rockville, MD) for the treatment of individuals age 18 or older with active, antibody-positive systemic lupus erythematosus (SLE), and for other indications. Belimumab is an intravenously or subcutaneously administered human monoclonal antibody drug that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation.

Clinical Indications

Medically Necessary:

Belimumab is considered medically necessary for individuals age 18 or older when all the following criteria are met prior to initiating therapy:

  1. Clinical diagnosis of SLE per the American College of Rheumatology (ACR) criteria; and
  2. Unequivocally positive ANA (anti-nuclear antibody) titre greater than or equal to 1:80 or anti-dsDNA (double stranded DNA antibody) greater than or equal to 30 IU/mL; and
  3. SLE is active as documented by a SELENA-SLEDAI score greater than or equal to 6 (see Appendix A) while on current treatment regimen; and
  4. There is no evidence of severe renal disease (proteinuria greater than 6 gm/day, serum creatinine greater than 2.5 mg/dl, or requiring renal dialysis); and
  5. There is no evidence of active central nervous system lupus (for example, psychosis or seizures); and
  6. SLE remains active while on corticosteroids, antimalarials, or immunosuppressants (alone or as combination therapy) for at least the last 30 days.

Continuing therapy with belimumab for treatment of SLE is considered medically necessary for individuals age 18 or older when all the following criteria are met:

  1. Clinical diagnosis of SLE per the ACR criteria; and
  2. There is documentation of previous improvement in disease activity following treatment with belimumab indicating a therapeutic response; and
  3. There is no evidence of severe renal disease (proteinuria greater than 6 gm/day, serum creatinine greater than 2.5 mg/dl, or requiring renal dialysis); and
  4. There is no evidence of active central nervous system lupus (for example, psychosis or seizures).

Not Medically Necessary:

Belimumab is considered not medically necessary for active SLE when all of the criteria specified above are not met, or when any of the following contraindications are present:

  1. Individuals treated with rituximab or any other B cell targeted therapy within the past year
  2. Individuals treated with IV cyclophosphamide within the past 180 days
  3. Individuals treated with intravenous immunoglobulin (Ig) within the past 90 days
  4. Individuals that have required prednisone at doses greater than 100 mg/day (or equivalent dose of another steroid) within the past 90 days
  5. Individuals that have required treatment for an acute or chronic infection within the past 60 days
  6. Individuals with human immunodeficiency virus (HIV) infection, hepatitis B virus infection, or hepatitis C virus infection.

Belimumab is considered not medically necessary for all other indications.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Injection, belimumab, 10 mg [Benlysta]



ICD-10 Diagnosis



Systemic lupus erythematosus (SLE)

Discussion/General Information

Belimumab is the first new drug approved for the treatment of active, autoantibody-positive, systemic lupus erythematosus (SLE) in 5 decades. Belimumab is administered via intravenous infusion at weeks 0, 2 and 4, and then every 4 weeks thereafter or once weekly via subcutaneous administration.

According to the Centers for Disease Control and Prevention (2018) there are approximately 1.5 million individuals with various forms of lupus nationally; nearly 90% are women, with African American women 3 times more likely to have the disease. SLE, often referred to as lupus, is a complex systemic form of the disease which attacks tissue and can affect joints, skin and other organs. This chronic life threatening autoimmune disease is currently treated with medicines such as aspirin, aristospan, corticosteroids, or plaquenil. Belimumab is a fully human monoclonal antibody which inhibits the biological activity of BLyS, otherwise known as B cell activation factor of the TNF family (BAFF), used in the treatment of active SLE.

Wallace and colleagues (2009), reported on a multicenter trial assessing the safety and efficacy of belimumab in combination with standard of care (SOC) in 449 adults with active SLE. Belimumab was given to 336 subjects and placebo administered to the remaining 113 subjects. Changes in these populations were compared by percent of change in Safety of Estrogen in Lupus Erythematosus National Assessment SLE Disease Activity Index (SELENA-SLEDAI) scores taken from the treatment group versus the placebo group. The author concluded:

In this phase II study, belimumab treatment combined with SOC therapy in SLE patients with active disease did not result in significant improvement compared with placebo as assessed by the co-primary endpoints of SELENA-SLEDAI score reduction at week 24 or reduction in time to first SLE flare over 52 weeks. Nevertheless, this trial provided evidence that belimumab was well tolerated and improved many secondary disease activity measures (SLE flares, PGA, SELENA-SLEDAI, SF-36 PCS) when added to SOC in a large (71.5%) subpopulation of serologically active patients. It generated a clinically meaningful hypothesis that provides the basis for the design of phase III confirmatory studies. The phase II study provided 4 valuable insights into the pharmacodynamics of belimumab, SLE disease activity, and trial design.

Belimumab (Benlysta) met its primary endpoint in two phase III trials in SLE. In 2010, belimumab was granted a priority review designation by the U.S. Food and Drug Administration (FDA) under the Prescription Drug User Free Act (PDUFA), and in March 2011 the manufacturer was granted approval to market belimumab in the United States. The data from one of the two pivotal trials were subsequently published by Navarra (2011). It should be noted that the primary outcome measure, the systemic lupus response index (SRI) was developed specifically for this study and was based in part on the results obtained from the Wallace (2009) phase II study. The SRI is a composite measure which has not been independently validated. The reliability and clinical significance of this metric remains unknown.

Navarra (2011) reported a phase III international study (Latin America, Asia-Pacific, and eastern Europe) using subjects randomized using a 1:1:1 ratio to belimumab 1 mg/kg (n=288), belimumab 10 mg/kg (n=290), or placebo (n=288); subjects were further stratified based on SELENA-SLEDAI score, proteinuria concentration and ethnic origin. The primary outcome response rate was assessed during 52 weeks using systemic lupus erythematosus response index (SRI), created to assess the improvement in disease activity without worsening of the overall disorder or development of substantial disease activity in new organ systems. The SRI response to belimumab was significant at both dosage levels [1 mg/kg (n=148) 51%, p=0.0129 and 10 mg/kg (n=167) 58%, p=0.0006]. With the SRI composite measure, a responder was defined as having a reduction of at least 4 points in the SELENA-SLEDAI score. Greater percentages of subjects on belimumab had a greater than or equal to 4 point reduction in this score [belimumab 1 mg/kg (53%), 10 mg/kg (58%) vs. placebo (46%)]. Individuals treated with both doses of belimumab reported no disease worsening compared to placebo, demonstrated by a reduction by 43%, 42%, & 55% in British Isles Lupus Assessment Group (BILAG) 1A flares or no more than one BILAG 2B organ domain flare at week 52. The Physician’s Global Assessment (PGA) reported greater results in the belimumab group defined as improvement from baseline (greater than 0.3) at week 52, belimumab 1 mg/kg (59%), belimumab 10 mg/kg (64%), and placebo (49%). The study population consisted of a sub-group of 30 African American subjects divided into 3 groups: belimumab 1 mg/kg (n=8), 3%; belimumab 10 mg/kg (n=11), 4%; placebo (n=11), 4%; the FDA requested additional post-market study of this subgroup of subjects. Nearly 69% of subjects in the study were on prednisone greater than 7.5 mg a day at the onset of the study. The prolonged use of high doses of corticosteroids has been identified as a cause of long-term damage and mortality in individuals with SLE. Although belimumab has steroid-sparing effects, it is currently unknown how the long-term side effects of belimumab treatment compare to those of chronic prednisone. Currently there are ongoing trials (Furie, 2009; Jacobi 2010) evaluating the long-term benefits and potential long-term harms of belimumab.

A phase III multicenter study reported by Furie and colleagues (2011) assessed the long-term efficacy of subjects age 18 or older with active SLE (per ACR criteria) receiving standard therapy regimen (stable treatment regimen included prednisone [or equivalent] at 7.5-40 mg/day alone or prednisone 0-40 mg/day combined with antimalarial drugs, nonsteroidal anti-inflammatory drugs, and/or immunosuppressive therapies) in combination with belimumab or placebo. Individuals presenting with positive ANA or anti-dsDNA positive SLE with SELENA-SLEDAI score of greater than or equal to 6 were randomized using a 1:1:1 ratio to receive belimumab 10 mg/kg (n=273), belimumab 1 mg/ kg (n=271), or placebo (n=275) intravenously. At week 52, belimumab 10 mg/kg met the primary efficacy endpoint with generated SLE Response Index (SRI) response rate (defined by a reduction of greater than or equal to 4 points in the SELENA-SLEDAI score, no new BILAG A organ domain score and no more than 1 BILAG B score, and no worsening [increase less than 0.3] in the physician’s global assessment score versus baseline) of 43.2%, belimumab 1 mg/kg (40.6%), or placebo 33.5%. At baseline, a subgroup of subjects (n=376) received doses greater than 7.5 mg/day of prednisone (or equivalent); during weeks 40-52 the prednisone dose was reduced greater than or equal to 25% to less than or equal to 7.5 mg/day in the belimumab 10 mg/kg group (17.5%), belimumab 1 mg/kg group (19.2%), and placebo group (12.7%). According to authors, the secondary efficacy endpoint, SRI response rate at week 76, demonstrated slightly greater response for belimumab 10 mg (39.1%) compared with belimumab 1 mg (38.5%) and placebo (32.4%), although the study was designed and powered to evaluate the SRI response rate at 52 weeks which makes the results statistically insignificant. The risk of severe flares (using the modified SLE Flare Index) reported at 52 and 76 weeks was reduced, belimumab 10 mg/kg (23%) (p=0.13) and belimumab 1 mg/kg (34%) (p=0.023). Study results report three deaths in the belimumab groups; one to ovarian cancer, one due to cardiac arrest after onset of multi-organ severe SLE flare and one due to unknown causes. There were six reported cases of malignancy among the belimumab groups. The authors reported:

The rate of malignancies (excluding non-melanoma skin cancers) per 100 patients-year in all patients with SLE treated with belimumab as of December 31, 2009 (odds ratio 0.45 [95% confidence interval 0.27-0.72]) is consistent with that reported in the literature for patients with SLE (odds ratio 0.53 [95% confidence interval 0.45-0.59)].

Belimumab in combination with standard therapy showed improvement in the SRI response rate, although further studies are needed to determine the long-term potential harm of belimumab.

Merrill and colleagues (2012) reported on a continuation phase II study which evaluated the safety and efficacy of belimumab plus standard therapy; the study evaluated long-term safety profile in participants with active SLE. A total of 364 active SLE participants completed the initial 52-week double-blind treatment period, receiving placebo or intravenous belimumab 1, 4 or 10 mg/kg, plus standard therapy (consisting of corticosteroids, antimalarial agents, and immunosuppressants, either alone or in combination). For the continuation study, 345 participants entered in a 24-week extension study; a total of 296 participants continued treatment with belimumab 10 mg/kg in the long-term continuation study. The safety data through 4 years of belimumab exposure (1165 cumulative patient/years) reported:

The most common adverse events included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year follow-up period. Rates of serious infection decreased from 5.9/100 patient/years to 3.4/100 patient/years, and no specific type of infection predominated.

Ongoing clinical trials are evaluating the use of belimumab in the treatment of rheumatoid arthritis (Furie, 2008; Stohl, 2013), Sjögren's syndrome (Mariette, 2015) and the administration of belimumab subcutaneously (once per week) in the treatment of SLE. Use of belimumab for these indications is not in accordance with generally accepted standards of medical practice.

Adverse Events and Warnings
The following are warnings and adverse events from the belimumab (Benlysta) Product Information Label (2018):

Precautions for use in specific populations:
The FDA approved labeling for belimumab (Benlysta) includes additional precautions for use in specific populations (Product Information Label, 2018):

Nursing Mothers
No information is available on the presence of belimumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Belimumab was detected in the milk of cynomolgus monkeys; however, due to species-specific differences in lactation physiology, animal data may not predict drug levels in human milk. Maternal IgG is known to be present in human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to belimumab are unknown. The lack of clear data during lactation precludes clear determination of the risk of Benlysta to an infant during lactation; therefore, the development and health benefits of breastfeeding should be considered along with the mother’s clear need for Benlysta, and any potential adverse effects on the breastfed child from Benlysta or from the underlying maternal conditions.

Females and Males of Reproductive Potential
Contraception: Following an assessment of benefit versus risk, if prevention of pregnancy is warranted, females of reproductive potential should use effective contraception during treatment and for at least 4 months after the after the final treatment.

Pediatric Use
Safety and effectiveness of Benlysta have not been established in children.

Geriatric Use
Clinical studies of Benlysta did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

In Trial 2 and Trial 3 (Benlysta 1 mg/kg and 10 mg/kg), response rates for the primary endpoint were lower for black subjects in the Benlysta group relative to black subjects in the placebo group. Use with caution in black/ African American patients.


ACR classification criteria of SLE: The ACR requires 4 of these 11 criteria simultaneously or in succession for an individual to be classified as having SLE:

SLE. Criterion


1. Malar rash

Fixed erythema over the malar eminences, tending to spare nasolabial folds

2. Discoid rash

Erythematous raised patches, may scar

3. Photosensitivity

Skin rash as a result of unusual reaction to sunlight

4. Oral ulcers

Usually painless

5. Arthritis

Non-erosive, involving one or more peripheral joints

6. Serositis

a. Pleuritis, OR b. Pericarditis

7. Renal disorders

a. Persistent proteinuria (>3+ or 500 mcg/day), OR b. Cellular casts in urine

8. Neurological disorder

a. Seizures, OR b. Psychosis

9. Hematological disorder

a. Hemolytic anemia, OR b. Leukopenia (<4000/cmm total), OR c. Lymphopenia (<1500/cmm or two or more occasions), OR d. Thrombocytopenia (<100,000/cmm)

10. Immunological disorder

a. Anti-DNA antibody to native DNA in abnormal titer, OR b. Anti-SM antibody to SM nuclear antigen, OR c. Anti-phospholipid antibodies

11. Anti-nuclear antibody

Abnormal titer of ANA excluding drug causes

Lupus nephritis: A kidney disorder that is a complication of systemic lupus erythematosus, disease often categorized on biopsy results.

Systemic lupus erythematosus (SLE): A systemic form of lupus attacking tissue with potential to affect joints, skin and other organs.


Peer Reviewed Publications:

  1. Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009; 61(9):1143-1151.
  2. Furie RA, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011; 66(12):3918-3930.
  3. Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008; 10(5):R109.
  4. Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol. 2014; 41(2):300-309.
  5. Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med. 2013; 368(16):1528-1535.
  6. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40(9):1725.
  7. Jacobi AM, Huang W, Wang T, et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 2010; 62(1):201-210.
  8. Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015; 74:526-531.
  9. Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum. 2012; 64(10):3364-3373.
  10. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011; 377(9767):721-731.
  11. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005; 353(24):2550–2558.
  12. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017; 69(5):1016-1027.
  13. Wallace DJ, Navarra S. Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus. 2013; 22(2):144-154.
  14. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009; 61(9):1168-1178.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Rheumatology (ACR). Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis & Rheumatism. 1999; 42(9):1785-1796.
  2. Belimumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2018. Accessed on November 27, 2017.
  3. Belimumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. June 13, 2018. Available at: Accessed on November 06, 2018.
  4. Benlysta® (belimumab) [Product Information]. Rockville, MD. Human Genome Sciences, Inc. June 22, 2018. Available at:,761043s002lbl.pdf. Accessed on November 06, 2018.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Systemic lupus erythematosus (SLE). Updated October 17, 2018. Available at: Accessed on November 06, 2018.
  2. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Handout on health: Systemic Lupus Erythematosus. June 2016. Available at: Accessed on November 06, 2018.


The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Discussion, References and Websites sections.



MPTAC review. Initial document development. Moved content from DRUG.00044 Belimumab (Benlysta®) to new clinical utilization management guideline document with the same title. Added wording addressing new subcutaneous formation of belimumab.

Appendix A

SELENA-SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) INSTRUMENT SCORE
Check box: if descriptor is present at the time of visit or in the preceding 10 days.
Check if







Recent onset (last 10 days). Exclude metabolic, infectious or drug cause,

or seizure due to past irreversible CNS damage.



Altered ability to function in normal activity due to severe disturbance in the perception of reality. Include hallucinations; incoherence; marked loose associations; impoverished thought content; marked illogical thinking; bizarre, disorganized or catatonic behavior. Exclude uremia and drug causes.


Organic brain syndrome

Altered mental function with impaired orientation, memory or other intellectual function, with rapid onset and fluctuating clinical features. Include clouding of consciousness with reduced capacity to focus, and inability to sustain attention to environment, plus at least 2 of the following: perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or decreased psychomotor activity. Exclude metabolic, infectious or drug causes.


Visual disturbance

Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, serous exudate or hemorrhages in the choroid, optic neuritis, scleritis or episcleritis. Exclude hypertension, infection or drug causes.


Cranial nerve disorder

New onset of sensory or motor neuropathy involving cranial nerves. Include vertigo due to lupus.


Lupus headache

Severe persistent headache: may be migrainous, but must be nonresponsive to narcotic analgesia.



New onset of cerebrovascular accident(s). Exclude arteriosclerosis or hypertensive causes.



Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages, or biopsy or angiogram proof of vasculitis.



More than 2 joints with pain and signs of inflammation (i.e., tenderness, swelling or effusion).



Proximal muscle aching/weakness, associated with elevated creatine phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis.


Urinary casts

Heme-granular or red blood cell casts.



>5 red blood cells/high power field. Exclude stone, infection or other cause.



New onset or recent increase of more than 0.5 gm/24 hours.



>5 white blood cells/high power field. Exclude infection.



Ongoing inflammatory lupus rash.



Ongoing abnormal, patchy or diffuse loss of hair due to active lupus.


Mucosal ulcers

Ongoing oral or nasal ulcerations due to active lupus.



Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural thickening due to lupus.



Classic and severe pericardial pain or rub or effusion, or electrocardiogram confirmation.


Low complement

Decrease in CH50, C3 or C4 below the lower limit of normal for testing laboratory.


Increased DNA binding

>25% binding by Farr assay or above normal range for testing laboratory.



□ >38oC. Exclude infectious cause.



<100,000 platelets/mm3.



<3,000 white blood cells/mm3. Exclude drug causes.

______ TOTAL SCORE (Sum of weights next to descriptors marked present)


Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005; 353(24):2550–2558.