Belimumab (Benlysta)

Number: 0818

Policy

Note: Requires Precertification.

Precertification of belimumab (Benlysta) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of belimumab (Benlysta), call (866) 752-7021, or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies to belimumab (Benlysta). For information on site of service for Benlysta infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers belimumab (Benlysta) medically necessary for the following indications:

   1. Systemic Lupus Erythematosus (SLE)

      For treatment of active SLE when all of the following criteria are met:

      1. Prior to initiating therapy, the member is positive for autoantibodies relevant to SLE; and
      2. The member is receiving a stable standard treatment for SLE with any of the following (alone or in combination):
         
         
         1. Glucocorticoids (e.g., prednisone, methylprednisolone, dexamethasone); or
         2. Antimalarials (e.g., hydroxychloroquine); or
         3. Immunosuppressants (e.g., azathioprine, methotrexate, mycophenolate, cyclosporine, cyclophosphamide).

   2. Active Lupus Nephritis

      For treatment of active lupus nephritis when all of the following criteria are met:

      1. Prior to initiating therapy, the member is positive for autoantibodies relevant to SLE; and
      2. Member has clinically active lupus renal disease and is receiving a stable standard induction and maintenance treatment for lupus nephritis (e.g., cyclophosphamide, mycophenolate mofetil, azathioprine, glucocorticoids).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of belimumab therapy medically necessary for members requesting reauthorization for an indication listed in Section I who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.

Dosage and Administration

Benlysta (belimumab) is available as the following:

• Intravenous infusion: 120 mg or 400 mg lyophilized powder in single-dose vials for reconstitution and dilution prior to intravenous infusion.
• Subcutaneous injection: 200 mg/mL single-dose prefilled autoinjector or single-dose prefilled syringe.

Systemic Lupus Erythematosus (SLE)

• Intravenous (IV) administration in adults and pediatrics with SLE: The recommended dosage for belimumab is 10 mg/kg IV over 1 hour every 2 weeks for the first 3 doses then every 4 weeks thereafter. Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.
  
  
• Subcutaneous administration in adults with SLE: The recommended dosage for subcutaneous belimumab is 200 mg once weekly. Subcutaneous dosing is not based on weight. Note: subcutaneous dosing of Benlysta has not been evaluated and is not approved for persons younger than 18 years of age.

Lupus Nephritis

• Intravenous administration in adults with lupus nephritis: The recommended dosage for belimumab is 10 mg/kg IV over 1 hour every 2 weeks for the first 3 doses then every 4 weeks thereafter. Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.
  

• Subcutaneous administration in adults with lupus nephritis: The recommended dosage regimen is a 400-mg dose (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. The dose is given via subcutaneous injection in the abdomen or thigh. The 400-mg dose for active lupus nephritis requires administration of 2 autoinjectors or 2 prefilled syringes. A person with lupus nephritis may transition from intravenous therapy with Benlysta to subcutaneous therapy any time after the person completes the first 2 intravenous doses. If transitioning, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last intravenous dose.

Source: GlaxoSmithKline, 2020a

Experimental and Investigational

Aetna considers belimumab therapy experimental and investigational for severe active central nervous system lupus (including seizures that are attributed to CNS lupus, psychosis, organic brain syndrome, cerebrovascular accident, cerebritis, or CNS vasculitis requiring therapeutic intervention within 60 days before initiation of belimumab).

Aetna considers the use of belimumab in combination with other biologics experimental and investigational.

Aetna considers combined rituximab and belimumab experimental and investigational for the treatment of immune thrombocytopenia.

Aetna considers belimumab therapy experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed in Section I has not been established:

• Antibody-associated vasculitis
• Antibody-mediated rejection in lung transplantation and kidney transplantation
• Anti-phospholipid antibody syndrome
• Autoimmune hepatitis
• Gout
• Graves' orbitopathy (ophthalmopathy)
• Immunosuppression following stem cell/solid organ transplantations
• Lung vasculitis
• Multiple sclerosis
• Myasthenia gravis
• Primary membranous nephropathy
• Psoriatic arthritis
• Renal vasculitis
• Retinal vasculitis
• Rheumatoid arthritis
• Sjogren syndrome
• Systemic sclerosis
• Uveitis
• Waldenstrom macroglobulinemia
• Wegener's granulomatosis (granulomatosis with polyangiitis)

Background

U.S. Food and Drug Adminstration (FDA)-Approved Indications

• Benlysta is indicated for the treatment of:

  • Patients aged 5 years and older with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy
  • Adult patients with active lupus nephritis who are receiving standard therapy.
    
    

• Limitations of Use - The efficacy of Benlysta has not been evaluated in patients with severe active central nervous system lupus. Benlysta has not been studied in combination with other biologics. Use of Benlysta is not recommended in these situations.

Benlysta (belimumab) is a human monoclonal antibody drug that specifically recognizes and inhibits the biological activity of B‐lymphocyte stimulator, or BLyS. BLyS is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. It is expressed as transmembrane protein on various cell types including monocytes, dendritic cells, and bone marrow stromal cells and is required for the development of B‐lymphocyte cells into mature plasma B cells. Plasma B cells produce anti‐bodies, the body's first line of defense against infection. In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies –antibodies that attack and destroy the body's own healthy tissues. The presence of autoantibodies appears to correlate with disease severity. Preclinical and clinical studies suggest that belimumab can reduce autoantibody levels in SLE.

Benlysta (belimumab) has been approved by the U.S. Food and Drug Administration (FDA) for the adjunctive treatment of active, autoantibody-positive, systemic lupus erythematosus (SLE). Belimumab has not been evaluated and is not recommended in patients with severe active lupus nephritis or severe active central nervous system lupus or in combination with other biologic products or cyclophosphamide.

Systemic lupus erythematosus (SLE) is a potentially fatal, autoimmune disease, which is characterized by clinical diversity, alerations in the disease activity over time, and aberrations in multiple components of the immune system including B cells, T cells, as well as cytokines and growth factors, especially the presence of anti-nuclear antibodies (ANA) that are found in over 90 % of the patients.  Moreover, anti-double-strand deoxyribonucleic acid (anti-dsDNA) antibodies are found in 50 to 90 % of the patients.  The prevalence of SLE worldwide is 4 to 250 per 100,000; the disease affects women disproportionately (approximately 90 % of the patients are female).  The incidence is most frequent in women aged 15 to 25 years.  The disease affects many parts of the body including the brain, heart, joints, kidneys, lungs, and the skin.  When SLE flares, it can present as chest pain, fatigue, fever, hair loss, rash, light sensitivity, as well as swelling in the joints and joint pain (Finnish Medical Society, 2007). 

Conventional treatments of SLE include anti-malarials (e.g., chloroquine and hydroxychloroquine), corticosteroids, and non-steroidal anti-inflammatory drugs (e.g., aspirin).  While therapeutic advances in immunosuppressive drugs (e.g., azathioprine, cyclophosphamide, methotrexate, mycophenolate) and support therapy have markedly improved survival, SLE still carries substantially increased rates of mortality and end stage renal disease, which are even more elevated in younger patients.  No new drugs have been approved for SLE in over 50 years.  Hence, a lot of hope and excitement has been generated by the development of biological agents designed to eliminate B cells either through direct killing (anti-B cell antibodies such as rituximab) or attrition by inhibition of survival (anti-B-lymphocyte stimulator BLyS [also known asBAFF] agents such as belimumab).  Belimumab is a human IgG1g antibody that is the first of the BLyS-specific inhibitor.  It blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells.  Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including auto-reactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.  Clinical trials of various phases have indicated that belimumab is beneficial for patients with SLE (Furie et al, 2008; Wallace et al, 2009; Jacobi et al, 2010; Navarra et al, 2011). 

In a phase I clinical study, Furie et al (2008) evaluated the safety, biological activity, and pharmacokinetics of belimumab in patients with SLE.  A total of 70 patients with mild-to-moderate SLE were randomized to receive placebo (n = 13) or belimumab (n = 57) at 4 different doses (1.0, 4.0, 10, and 20 mg/kg body weight) as a single infusion or two infusions 21 days apart.  Patients were followed for 84 to 105 days to assess adverse events, pharmacokinetics, peripheral blood B-cell counts, serology, and SLE disease activity.  Data from the study were summarized using descriptive statistics.  Chi-square type tests were used to analyze discrete variables.  The Kruskal-Wallis test, the Wilcoxon test, and the analysis of co-variance were used to analyze the continuous variables, as appropriate.  The analysis was performed on all randomized patients who received study agent.  The incidences of adverse events and laboratory abnormalities were similar among the belimumab and placebo groups.  Belimumab pharmacokinetics were linear across the 1.0 to 20 mg/kg dose range.  Long terminal elimination half-life (8.5 to 14.1 days), slow clearance (7 ml/day per kg), and small volume of distribution (69 to 112 ml/kg) were consistent with a fully human antibody.  Significant reductions in median percentages of CD20+ B cells were observed in patients treated with a single dose of belimumab versus placebo (day 42: p = 0.0042; and day 84: p = 0.0036) and in patients treated with 2 doses of belimumab versus placebo (day 105: p = 0.0305); SLE disease activity did not change after 1 or 2 doses of belimumab.  The authors concluded that belimumab was well-tolerated and reduced peripheral B-cell levels in SLE patients.

In a phase II, randomized, double-blind, placebo-controlled, dose-ranging study, Wallace and colleagues (2009) evaluated the safety, tolerability, biological activity, and effectiveness of belimumab in combination with standard of care therapy (SOC) in patients with active SLE.  Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score greater than or equal to 4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study.  Co-primary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare.  Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed.  Reductions in SELENA-SLEDAI scores from baseline were 19.5 % in the combined belimumab group versus 17.2 % in the placebo group.  The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group.  However, the median time to first SLE flare during weeks 24 to 52 was significantly longer with belimumab treatment (154 versus 108 days; p = 0.0361).  In the subgroup (71.5 %) of serologically active patients (ANA titer greater than or equal to 1:80 and/or anti-dsDNA greater than or equal to 30 International Units/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8 % versus -14.2 %; p = 0.0435), physician's global assessment (-32.7 % versus -10.7 %; p = 0.0011), and Short Form-36 physical component score (+3.0 versus +1.2 points; p = 0.0410).  Treatment with belimumab resulted in a 63 to 71 % reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4 % reduction in anti-dsDNA titers (p = 0.0017) by week 52.  The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.  The authors concluded that belimumab was biologically active and well-tolerated.  The effect of belimumab on the reduction of SLE disease activity or flares was not significant.  However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

Jacobi and co-workers (2010) examined the effects of long-term BLyS inhibition in patients with SLE.  A total of 17 subjects with SLE who were enrolled in a clinical trial of belimumab plus SOC were studied.  Phenotypic analysis of lymphocytes was performed using flow cytometry.  Circulating antibody-secreting cells were enumerated using enzyme-linked immunospot assay.  Serum was analyzed by enzyme-linked immunosorbent assay using an antibody that recognizes products of the V(H)4-34 gene.  Lymphocyte counts, Ig levels, and anti-dsDNA antibody levels were available as part of the clinical trial analyses.  Samples were collected on days 0, 84, 168, 365, and 532 and after day 730.  The total number of B cells started to decrease from baseline between days 84 and 168.  This was due to a decrease in naive and transitional B cells.  CD27+IgD+ memory B cells and plasmablasts decreased only after 532 days, whereas CD27+IgD- memory B cells were not affected, and there were no changes in T cells.  Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti-DNA antibodies, or V(H)4-34 antibodies during the study.  Patients with SLE had more IgM-, IgG-, and autoantibody-producing B cells than did normal controls on day 0.  There was only a modest decrease in the frequency of total IgM-producing, but not IgG-producing, cells on days 365 and 532, consistent with the phenotypic and serologic data.  The authors concluded that these findings confirm the dependence of newly formed B cells on BLyS for survival in humans.  In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.

In a randomized, multi-center, placebo-controlled, phase III trial, Navarra and associates (2011) evaluated the safety and effectiveness of belimumab in patients with active SLE.  Patients (aged greater than or equal to 18 years) who were sero-positive with scores of at least 6 on the SELENA-SLEDAI were enrolled in the study.  Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 hr on days 0, 14, and 28, and then every 28 days until 48 weeks, with SOC.  Patients, investigators, study coordinators, and sponsors were masked to treatment assignment.  Primary efficacy end point was improvement in the SLE Responder Index (SRI) at week 52 (reduction greater than or equal to 4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [less than 0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline.  Method of analysis was by modified intention-to-treat.  A total of 867 patients were randomly assigned to belimumab 1 mg/kg (n = 289) or 10 mg/kg (n = 290), or placebo (n = 288); 865 were treated and analyzed in the belimumab (1 mg/kg, n = 288; 10 mg/kg, n = 290) and placebo groups (n = 287).  Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51 %], odds ratio 1.55 [95 % confidence interval [CI]: 1.10 to 2.19]; p = 0·0129) and 10 mg/kg (167 [58 %], 1.83 [1.30 to 2.59]; p = 0·0006) than with placebo (125 [44 %]) at week 52.  More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53 %], 1.51 [1.07 to 2.14]; p = 0·0189) and 10 mg/kg (169 [58 %], 1.71 [1.21 to 2.41]; p = 0·0024) than with placebo (132 [46 %]).  More patients given belimumab 1 mg/kg (226 [78 %], 1.38 [0.93 to 2.04]; p = 0·1064) and 10 mg/kg (236 [81 %], 1.62 [1.09 to 2.42]; p = 0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73 %]).  No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79 %], 1.68 [1.15 to 2.47]; p = 0·0078) and 10 mg/kg (231 [80 %], 1.74 [1.18 to 2.55]; p = 0·0048) than with placebo (199 [69 %]).  Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8 %), 13 (4 %), and 17 (6 %) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in 2 (less than 1 %), 2 (less than 1 %), and no patients, respectively.  No malignant diseases were reported.  The authors concluded that belimumab has the potential to be the first targeted biological treatment that is approved specifically for SLE, providing a new option for the management of this important prototypic autoimmune disease.

On March 8, 2011, the U.S. Food and Drug Administration approved belimumab (Benlysta) for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy, including anti-malarials, corticosteroids, immunosuppressives, and non-steroidal anti-inflammatory drugs.  The label for Benlysta includes the following limitations of use: The efficacy of belimumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus, and has not been studied in combination with other biologics or intravenous cyclophosphamide.  Belimumab is administered intravenously over a 1-hour period; it should not be administered with live vaccines.  The most common side effects associated with the use of belimumab include diarrhea, fever, and nausea.  Patients also commonly experienced infusion reactions; thus, pre-treatment with an anti-histamine should be considered.  Belimumab is approved at a dosage of 10 mg/kg of body weight to be given at 2-week intervals for the first 3 doses and 4-week intervals thereafter.  In several randomized controlled trials examining the effectiveness of belimumab in patients with SLE, the durations of therapy were 52 and 76 weeks (Phung, 2011).  In a clinical study of belimumab submitted to the FDA for approval, active SLE disease was defined as a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index) score of equal to or greater than 4, and positive autoantibody test results (anti-nuclear antibody [ANA] and/or anti-double-stranded DNA [anti-dsDNA]) at screening.

Belimumab has also been studied in the treatment of other autoimmune diseases such as lupus nephritis, multiple sclerosis, and rheumatoid arthritis (Aran and Putterman, 2008; Hawker, 2008; Bingham, 2008).  Furthermore, belimumab is being considered as one of the novel strategies in immunosuppression following stem cell/solid organ transplantations (Webber et al, 2011).  However, in the absence of evidence based on large, randomized, placebo-controlled trials, the role of belimumab for these indications has yet to be established.

The American College of Rheumatology's guidelines for screening, treatment, and management of lupus nephritis (Hahn et al, 2012) notes that alternative therapies (e.g., rituximab, tacrolimus, belimumab, calcineurin inhibitors) were considered but no consensus for recommendation was reached.

Khattri and colleagues (2012) stated that the increased awareness of the role of humoral immunophysiology in anti-phospholipid syndrome (APS) has aroused interest in B cells as therapeutic targets in this disease.  These researchers reviewed the literature on B cell-directed therapies in human and experimental APS.  The clinical data were limited to B cell depletion with rituximab and comprised case reports and case series.  Murine studies include use of modulators of B cell function (e.g., belimumab and abatacept).  In both human and murine studies, B cell-directed therapies appeared to have clinical and serologic beneficial effects including a decrease in the anti-phospholipid antibody titers after treatment.  The authors concluded that randomized controlled trials are needed to examine if B cell depletors and/or B cell modulators can be effective agents for treating patients with APS.

O'Neill and Scully (2013) noted that biologic therapy has a potential to benefit patients with orofacial manifestations of Sjogren syndrome (SS).  The most appropriate use of biologics would appear to be in patients with severe or multi-system features of SS, but their use early in the pathogenesis has the potential to prevent disease progression.  Tumor necrosis factor-alpha blockade has not proven effective in SS.  B-cell depletion using rituximab has been of benefit, mainly in relation to extra-glandular features, and to some extent in relation to hypo-salivation where there is still residual salivary function.  Rituximab is also effective in the treatment of SS-associated (extra-salivary) lymphomas, although the therapeutic response in salivary lymphoma is poorer.  Rituximab is given as a single or periodic intravenous infusion.  Potential adverse effects exist, notably infusion reactions and infection, and so a full risk/benefit analysis is indicated for prospective patients.  The authors concluded that further studies of rituximab in SS are ongoing, and newer agents under trial include belimumab.

Jin and Ding (2013) summarized up-to-date pharmacological and clinical data of belimumab in the treatment of rheumatoid arthritis (RA).  A literature search was performed on PubMed using keywords, including belimumab, LymphoStat-B, benlysta, BLyS inhibitor, rheumatoid arthritis and autoimmune disease.  References of relevant studies were searched by hand.  Abstracts of international conferences up to October 2012 were also included.  Belimumab was well-tolerated in the treatment of RA over 24 weeks.  It significantly increased American College of Rheumatology (ACR)20 responses at week 24, especially in patients with high disease activity, positive rheumatoid factor, no anti-tumor necrosis factor (TNF) treatment experience and those who had failed methotrexate therapy.  However, belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single phase II clinical trial of RA.  The authors concluded that these results suggested that the clinical effectiveness of belimumab for RA needs to be further investigated in future clinical trials.  Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA.

In a single-arm, phase II clinical trial, Bishton et al (2013) evaluated the safety and activity of belimumab in 12 patients with Waldenstrom macroglobulinemia (WM).  A total of 10 patients had stable disease with therapy, although no objective responses were seen.  Correlative studies showed patients to have low or undetectable baseline serum levels of B-lymphocyte stimulator, with the administration of belimumab having no effect on B-cell numbers.  The authors concluded that belimumab cannot be recommended as a single-agent therapy for the treatment of symptomatic WM, although further evaluation in combination with other agents would be justified.

Furuta and Jayne (2014) noted that the current standard therapy for anti-neutrophil cytoplasm antibody-associated vasculitis (AAV), high-dose glucocorticoid and cyclophosphamide followed by azathioprine, has improved the disease prognosis.  However, there are still unmet needs.  For example, reducing relapse risk and glucocorticoid toxicity; newer therapies are needed.  These researchers stated that potential newer drugs are emerging following a better understanding of disease mechanisms and the availability of targeted therapies to B cells, T cells, pro-inflammatory cytokines and complement.  Rituximab has proven efficacy in remission induction therapy for AAV, and 2 trials with rituximab as remission maintenance therapy are ongoing.  Clinical trials evaluating mycophenolate mofetil as remission induction therapy, gusperimus, belimumab and complement factor C5a inhibition are also ongoing, and many other potential candidates are being investigated both clinically and experimentally.  The authors concluded that B-cell therapy is now an established treatment in AAV and several other therapies are under evaluation.  However, the unmet need in vasculitis therapy remains large and newer therapies either alone or in combination will need to both improve efficacy and permit reductions in glucocorticoid and immunosuppressive exposure.

Schwartz et al (2014) stated that renal involvement is a major cause of morbidity and mortality in SLE.  These researchers provided an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis.  Localized long-lived plasma cells have been identified as playing an important role in lupus nephritis.  In addition, the roles of aberrant expression of microRNAs and pro-inflammatory cytokines have been explored.  Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none has been yet validated for clinical use.  Biomarker panels may turn out to be more accurate than each individual component.  Biologic agents for the treatment of lupus nephritis are being studied, including belimumab which was recently approved for non-renal SLE.  Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of lupus nephritis.  The authors concluded that lupus nephritis is a potentially devastating complication of SLE.  Immune cells, cytokines, and epigenetic factors have all been recently implicated in lupus nephritis pathogenesis.  These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease.

In a review on “The future of uveitis treatment”, Lin and colleagues (2014) listed belimumab as one of the emerging therapies for the treatment of uveitis.  Furthermore, an UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2014) does not mention belimumab as a therapeutic option.

Selmi and colleagues (2014) stated that as the understanding of the pathogenesis of autoimmune diseases is growing, new therapies are being developed to target disease-specific pathways. Since the introduction of etanercept in 1998, several biotechnological agents have been developed, most of them indicated in the treatment of RA, but also psoriatic arthritis. Most currently available molecules target TNF-alpha with different strategies (i.e., etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol), interleukin (IL)-6 (tocilizumab), CTLA-4 (abatacept), and B cells (rituximab, belimumab) as they are key mediators in the cascade of inflammation. Further, small molecules have been recently developed to target intra-cellular signaling, such as janus kinases for tofacitinib, the first FDA-approved small molecule for RA. Most novel treatments are being developed for arthritis with specific differences between RA and psoriatic arthritis, as well as for SLE, following the approval of belimumab. Finally, biologic therapies are effective also in gout, mainly targeting IL-1 to block the inflammasome. These researchers described the new and upcoming treatment options for RA, psoriatic arthritis, SLE, and gout to dissect what one should be aware of when discussing these new and promising molecules.

In a phase II clinical trial, De Vita and colleagues (2015) examined the safety and effectiveness of long-term treatment of SS with belimumab. Patients with primary SS were included in the BELISS study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received intravenous belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Safety and effectiveness were analyzed during the 1-year period of treatment. Among the 30 patients recruited, 28 were evaluated at week 28 as already reported; 19 terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28; 13 of the 15 responders at week 28 also responded at week 52 (86.7 %). The improvement in the EULAR Sjogren's Syndrome Disease Activity Index and EULAR Sjogren's Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjogren's Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmer's test and the focus score of salivary biopsy did not change. Safety of treatment was good. The authors concluded that long-term treatment with belimumab may be beneficial in SS; randomized, double-blind, controlled studies in larger populations are encouraged.

In April 2019, Benlysta, for intravenous use, was FDA-approved for use in pediatric patients aged 5 years and older with active, autoantibody positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. (GSK, 2019).

Antibody-Mediated Rejection in Kidney Transplantation

Banham and colleagues (2018) stated that B cells produce allo-antibodies and activate allo-reactive T cells, negatively affecting kidney transplant survival.  By contrast, regulatory B cells are associated with transplant tolerance.  Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimizing infection risk.  B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients.  These researchers examined the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients.  They used an experimental medicine study design with multiple secondary and exploratory end-points to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment.  In a randomized, double-blind, placebo-controlled, phase-II clinical trial, these researchers employed belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at 2 centers.  Subjects were eligible if they were aged 18 to 75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression.  They were randomly assigned (1:1) to receive either intravenous belimumab 10 mg/kg body weight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of 7 infusions.  The co-primary end-points were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analyzed in all patients who received a transplant and at least 1 dose of drug or placebo (the modified intention-to-treat [mITT] population).  Between September 13, 2013, and February 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n = 14) or placebo (n = 14); 25 patients (12 [86 %] patients assigned to the belimumab group and 13 [93 %] patients assigned to the placebo group) received a transplant and were included in the mITT population.  These investigators observed similar proportions of adverse events (AEs) in the belimumab and placebo groups, including serious infections (1 [8 %] of 12 in the belimumab group and 5 [38 %] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and 2 [15 %] in the placebo group during the 6-month follow-up).  In the on-treatment phase, 1 patient in the placebo group died because of fatal myocardial infarction (MI) and acute cardiac failure.  The co-primary end-point of a reduction in naive B cells from baseline to week 24 was not met.  Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted MD between the belimumab and placebo treatment groups -34.4 cells/μL, 95 % CI: -109.5 to 40.7).  The authors concluded that belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral allo-immunity.  These preliminary findings need to be validated by well-designed studies.

Antibody-Mediated Rejection in Lung Transplantation

Hulbert and colleagues (2018) stated that there is increasing recognition of the importance of antibody-mediated rejection (AMR) after lung transplantation.  The development of donor-specific antibodies, a key feature of AMR, occurs in approximately 30 % of lung transplant recipients and is associated with poor post-transplant outcomes.  These investigators high-lighted recently developed AMR diagnostic criteria in lung transplantation, potential mechanisms that mediate the development of AMR, and discusses current and emerging treatment strategies for this significant, graft-limiting complication.  A major advance is the development of consensus guidelines to precisely define AMR among lung transplant.  Regimens for the treatment of AMR continue to evolve with varying success reported with regards to antibody clearance and improving clinical outcomes.  A multi-modality treatment approach was common, typically involving a combination of intravenous immune globulin (IVIG), plasmapheresis (PP), rituximab, and bortezomib or carfilzomib.  The authors concluded that recent studies suggested several new agents including tocilizumab, belimumab, daratumumab, plerixafor, and C1 esterase inhibitor as potentially novel and effective therapies to employ in AMR treatment.  These investigators noted that despite advancements in the diagnosis of AMR through well-defined consensus guidelines, there is limited evidence to guide treatment.  Current data suggests that conventional approaches are of sub-optimal efficacy, but emerging therapeutic agents with diverse biological mechanisms offer promise for improved AMR treatment.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

In a double-blind, multi-center, placebo-controlled study, Jayne and colleagues (2019) examined the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).  Patients with AAV (ages greater than or equal to 18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (less than or equal to 10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with RTX or cyclophosphamide along with glucocorticoids.  The primary end-point was time to first protocol-specified event (PSE), with 1st PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of greater than or equal to 6, presence of greater than or equal to 1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen).  Vasculitis relapse was defined as the PSE of either a BVAS activity score of greater than or equal to 6 or receipt of prohibited medications for vasculitis.  Changes in treatment practice led to truncation of the study population from approximately 300 patients to approximately 100 patients.  The ITT population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in RTX-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline.  Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95 % CI: 0.44 to 2.59; p = 0.884) or vasculitis relapse (adjusted HR 0.88, 95 % CI: 0.29 to 2.65; p = 0.821).  The overall rate of PSEs was low (11 [21.2 %] of 52 patients receiving placebo, 10 [18.9 %] of 53 patients receiving belimumab).  Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type.  All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA-associated vasculitis with cyclophosphamide-induced disease remission; AEs occurred in 49 (92.5 %) of 53 patients receiving belimumab and 43 (82.7 %) of 52 patients receiving placebo, with no new safety concerns.  The authors concluded that belimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

Bala and colleagues (2020) stated that AAV are a group of rare auto-inflammatory diseases that affects mainly small vessels; it includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA).  Anti-cytokine targeted therapy uses biological agents capable of specifically targeting and neutralizing cytokine mediators of the inflammatory response.  In a Cochrane review, these investigators examined the benefits and harms of anti-cytokine targeted therapy for adults with AAV.  They searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), Medline and Embase up to August 16, 2019.  They also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers; RCTs or controlled clinical trials of targeted anti-cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti-cytokine therapy of different type or dose were selected for analysis.  These researchers used standard methodological procedures expected by Cochrane.  They included 4 RCTs with a total of 440 subjects (mean age of 48 to 56 years).  These researchers analyzed the studies in 3 groups: First group -- mepolizumab (300 mg; 3 separate injections every 4 weeks for 52 weeks) versus placebo in patients with relapsing or refractory EGPA.  Second group -- belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last patient was randomized) or etanercept (25 mg twice-weekly) with standard therapy (median of 25 months) versus placebo with standard therapy (median of 19 months) in patients with GPA/MPA.  Third group -- infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m2 on days 1, 8, 15 and 22) in patients with refractory GPA for up to 12 months.  None of the studies was assessed as low risk of bias in all domains: 1 study did not report randomization or blinding methods clearly; 3 studies were at high risk and 1 study was at unclear risk of bias for selective outcome reporting.  One trial with 136 subjects with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow-up and observed 1 death in the mepolizumab group (1/68, 1.5 %) and none in the placebo group (0/68, 0 %) (Peto odds ratio (OR) 7.39, 95 % CI: 0.15 to 372.38; low-certainty evidence).  Low-certainty evidence suggested that more subjects in the mepolizumab group had greater than or equal to 24 weeks of accrued remission over 52 weeks compared to placebo (27.9 % versus 2.9 %; risk ratio (RR) 9.5, 95 % CI: 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1 % mepolizumab versus 1.5 % placebo; RR 13.0, 95 % CI: 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95 % Cl: 4 to 13).  Mepolizumab probably decreases risk of relapse (55.8 % versus 82.4 %; RR 0.68, 95 % CI: 0.53 to 0.86; NNTB 4, 95 % CI: 3 to 9; moderate-certainty evidence).  There was low-certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9 % versus 1.5 %; RR 2.00, 95 % CI: 0.19 to 21.54); disease flares were not measured.  Based on 2 trials with different follow-up periods (mean of 27 months for etanercept study; up to 4 years for belimumab study) including people with GPA (n = 263) and a small group of subjects with MPA (n = 22) analyzed together, these investigators found low-certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy did not increase or reduce mortality (3.4 % versus 1.4 %; Peto OR 2.45, 95 % CI: 0.55 to 10.97).  Etanercept may have little or no effect on remission (92.3 % versus 89.5 %; RR 0.97, 95 % CI: 0.89 to 1.07), durable remission (70 % versus 75.3 %; RR 0.93, 95 % CI: 0.77 to 1.11; low-certainty evidence) and disease flares (56 % versus 57.1 %; RR 0.98, 95 % CI: 0.76 to 1.27; moderate-certainty evidence).  Low-certainty evidence suggested that belimumab did not increase or reduce major relapse (1.9 % versus 0 %; RR 2.94, 95 % CI: 0.12 to 70.67) or any AE (92.5 % versus 82.7 %; RR 1.12, 95 % CI: 0.97 to 1.29).  Low-certainty evidence suggested a similar frequency of serious or severe AEs (47.6 % versus 47.6 %; RR 1.00, 95 % CI: 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2 %) compared to the placebo group (4.2 %), RR 2.66, 95 % CI: 1.07 to 6.59).  One trial involving 17 subjects with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months.  One subject died in each group (Peto OR 0.88, 95 % CI: 0.05 to 15.51; 11 % versus 12.5 %).  There were very low-certainty evidence for remission (22 % versus 50 %, RR 0.44, 95 % Cl: 0.11 to 1.81) and durable remission (11 % versus 50 %, RR 0.22, 95 % CI: 0.03 to 1.60), any severe AE (22.3 % versus 12.5 %; RR 1.78, 95 % CI: 0.2 to 16.1) and withdrawals due to AEs (0 % versus 0 %; RR 2.70, 95 % CI: 0.13 to 58.24).  Disease flare/relapse and the frequency of any AE were not reported.  The authors found 4 studies but concerns regarding risk of bias and small sample sizes precluded firm conclusions.  They found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreased disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission.  There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably evaluate these outcomes.  Mepolizumab may result in little to no difference in mortality.  However, there were very few events.  In patients with GPA (and a small subgroup of patients with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs.  Etanercept may have little or no impact on durable remission and probably does not reduce disease flare.

Autoimmune Hepatitis

Arvaniti and colleagues (2020) stated that autoimmune hepatitis (AIH) is a disease of unknown etiology with a favorable response to immunosuppression.  However, in the clinic, it appeared that less than 50 % of patients achieve complete response on standard treatment.  Serum B cell-activating factor (BAFF) levels are elevated in patients with AIH and are likely to contribute to disease pathogenesis.  Since belimumab has been shown to be effective in other autoimmune diseases, these investigators examined its use as a 3rd-line add-on therapeutic option in patients with advanced AIH who did not respond to conventional treatment.  They reported for the 1st time 2 patients, a 27-year old woman and a 58-year old man, both with AIH-related compensated cirrhosis at diagnosis, who were refractory to standard immunosuppressive therapies and received add-on 3rd-line therapy with belimumab.  Both patients achieved a complete response and remained in remission while receiving low-dose corticosteroids.  No AEs related to belimumab and/or disease decompensation were observed.  The authors concluded that these preliminary findings indicated belimumab as a promising therapeutic option for patients with AIH and refractory and advanced liver-related fibrosis.

Combined Rituximab and Belimumab for the Treatment of Immune Thrombocytopenia

Mahevas and colleagues (2020) noted that B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells.  From results obtained in mouse models, these researchers hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at 1 year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells.  In a prospective, single-arm, single-center, phase-IIb clinical trial, these investigators examined the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, 2 weeks apart, combined with 5 infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP.  The primary end-point was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition.  A total of 15 non-splenectomized adults, 9 (60 %) with persistent IPT and 6 (40 %) with chronic ITP, were included.  No severe AE, infection, or severe hypogammaglobulinemia was observed; 13 patients achieved an initial overall response.  At W52, 12 (80 %) patients achieved an overall response, including 10 (66.7 %) with complete response.  When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell re-population appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy.  The authors concluded that combining rituximab and belimumab appeared to be a promising strategy in ITP, with high efficacy and acceptable safety.  These investigators noted that the major drawbacks of this single-center, pilot study were the open design and small sample size (n = 15). They stated that these preliminary findings should be validated in a prospective, randomized, double-blind, multi-center trial.

Cutaneous Lupus

Vashisht and colleagues (2017) presented their experience of using belimumab for the management of cutaneous lupus at their center.  These researchers studied 5 patients with significant SLE skin manifestations.  All patients met 1997 ACR SLE criteria and had failed multiple medications to control their skin disease; PGA, SLEDAI, and Cutaneous LE disease Area and Severity Index (CLASI) were recorded before and 16 weeks after belimumab treatment.  Belimumab was added to concomitant standard therapy.  All 5 patients demonstrated marked clinical improvement following belimumab treatment.  The average time to clinical improvement after treatment initiation was 8 to 12 weeks; SLEDAI scores (median, range) improved in all the patients ((2, 2 to 6) to (0, 0 to 4); p = 0.025); PGA scores (median, range) were better in all patients ((3, 2 to 3) to (1, 0 to 1); p = 0.039); CLASI activity scores (median, range) improved dramatically in all patients ((17, 9 to 31) to (3, 2 to 14); p = 0.043).  There was no worsening of the CLASI damage scores.  The mean daily prednisone dose decreased significantly from 31 mg (± 18.8) at baseline to 3 mg (± 2.7) (p = 0.042).  The authors concluded that in this case series, the addition of belimumab to standard therapy improved the signs and symptoms of refractory cutaneous lupus.  This was one of the first reports highlighting the potential utility of this medication for the treatment of severe skin involvement in SLE refractory to conventional therapies.  Moreover, they stated that additional studies are needed to evaluate the use of belimumab in the treatment of cutaneous lupus.

Discoid Lupus

Chong et al (2014) stated that B-cell activating factor of the TNF family (BAFF) promotes the maturation and survival of B cells.  Because BAFF levels are elevated in systemic lupus erythematosus (SLE) patients, BAFF has been the target of emerging therapies for SLE, such as belimumab.  Levels of BAFF and its receptors in discoid lupus erythematosus (DLE) patients are unknown.  These researchers compared skin and blood mRNA and protein levels of BAFF and its receptors BAFF-R, TACI, and BCMA in DLE subjects with (DLE+/SLE+ (n = 28)) and without SLE (DLE+/SLE- (n = 35)), psoriasis subjects (n = 11), and normal subjects (n = 42).  They used quantitative real-time PCR to measure blood and skin BAFF, BAFF-R, TACI, and BCMA mRNA, sandwich ELISAs to measure sera BAFF, and immunohistochemistry to evaluate BAFF and BAFF-R skin protein expression.  BAFF mRNA and protein levels were highest in DLE+/SLE+ blood, followed by DLE+/SLE-, psoriasis, and normal blood.  BAFF protein also correlated with anti-nuclear antibodies, and auto-antibodies against double-stranded DNA, single-stranded DNA, and ribonucleoprotein, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in DLE patients.  While showing no difference between DLE+/SLE+ and DLE+/SLE- skin, BAFF and its receptors mRNA were up-regulated in DLE skin versus normal and psoriasis skin; DLE skin had higher percentages of BAFF-R⁺ inflammatory cells, likely T cells and macrophages, than psoriasis and normal skin.  The authors concluded that BAFF may be a serologic marker of systemic disease in DLE patients; BAFF and its receptors were elevated in DLE skin, suggesting that targeted therapies against these proteins could treat refractory DLE patients.

Ugarte and colleagues (2018) evaluated the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with SLE and refractory joint and/or skin disease.  Mepacrine was added to 46 SLE patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs (n = 24), hydroxychloroquine + prednisone (n = 16), hydroxychloroquine + prednisone + retinoids (n = 2), hydroxychloroquine alone (n = 1), hydroxychloroquine + 1 immunosuppressive drug (n = 1), hydroxychloroquine + prednisone + 1 immunosuppressive drug + belimumab (n = 1) or hydroxychloroquine + prednisone + belimumab (n = 1).  The outcome variable was the clinical response, either complete or partial, based on clinical judgement.  The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the SLEDAI score were additionally used.  A total of 91 % patients showed complete/partial response, with similar rates among those with joint or skin disease.  In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen.  There also was a statistically significant decrease in the SLEDAI.  The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/day (p = 0.001).  Prednisone could be discontinued in 20 % of patients.  No serious adverse events (AEs) were seen.  Smoking was the only predictor of complete response.  The authors concluded that in the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses.  The fact that smokers responded better opened the door to further studying the combination of mepacrine-hydroxychloroquine as a 1st-line therapy in such patients.  (Discoid lupus was one of the keywords listed in the present study).

An UpToDate review on “Initial management of discoid lupus and subacute cutaneous lupus” (Clarke, 2018a) does not mention belimumab as a therapeutic option.  Furthermore, an UpToDate review on “Management of refractory discoid lupus and subacute cutaneous lupus” (Clarke, 2018b) states that “Multiple other medications have been used for subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE).  With the exception of clofazimine, data supporting these therapies [including belimumab] are limited … The effect of belimumab in cutaneous LE has not been well studied; however, in a series of 5 patients with SLE and acute cutaneous lupus erythematosus, SCLE, and/or DLE, all had significant improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) disease activity scores with the addition of intravenous belimumab to standard treatment.  The average time to clinical improvement was 4 months, and marked improvement occurred as early as 8 weeks.   Serious potential adverse effects of belimumab include hypersensitivity reactions, infections, and depression”.

Early Diffuse Cutaneous Systemic Sclerosis

In a randomized, double-blind, placebo-controlled, pilot trial, Gordon and colleagues (2018) evaluated the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF).  In this 52-week, investigator-initiated, single-center, double-blind, placebo-controlled, pilot study, a total of 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo.  These investigators assessed safety, efficacy, and differential gene expression.  In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5 to 31) to 18 (IQR 11 to 23) (p = 0.039).  In the placebo group, the median MRSS decreased from 28 (IQR 22 to 28) to 21 (IQR 14 to 25) (p = 0.023).  The median change in MRSS was -10 (IQR -13 to -9) in the belimumab group and -3.0 (IQR -15 to -1) in the placebo group (p = 0.411).  There were no significant differences between the groups in the number of AEs.  A significant decrease in expression of B cell signaling and pro-fibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group.  The authors concluded that patients in both treatment groups experienced significant improvements in MRSS.  The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study; AEs were similar between the groups.  Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab was associated with a significant decrease in pro-fibrotic genes and pathways.  These researchers stated that additional studies are needed to determine the role of belimumab in the treatment of dcSSc.

Graves' Orbitopathy (Ophthalmopathy)

Salvi and Covelli (2019) noted that B cells have multiple actions on different phases of an immune reaction, mainly resulting in B and T cell-interaction (help), production of cytokines, regulation of dendritic cells and down-regulation of regulatory B cells.  The effectiveness of B cell depletion therapy is probably due to blockade of the antigen-presenting function of B cells, occurring very early in the setting of autoimmune reactions.  B cells undergo a maturation process from stem cells during which the CD 20 antigen, which is the target of RTX, is expressed from the stage of pre-B cells to mature and memory B cells, but not on plasma cells.  During the maturation process, the cytokine B cell stimulating factor (BAFF) induces maturation of B cells and expansion of clones to produce plasma cells and eventually antibodies.  The effect of RTX in Graves' orbitopathy (GO) is rather rapid, with significant improvement of the disease already 4 to 6 weeks after the first RTX infusion.  Based on the evidence of significant lymphocytic infiltration in the orbits of patients with active GO, it is reasonable to postulate that RTX may cause depletion of B cells and block their antigen-presenting cell mechanism.  Since it has been reported that serum BAFF concentrations are elevated in hyper-thyroid GD patients and that BAFF is expressed on the thyrocytes of patients with either autoimmune disease or nodular goiter, the hypothesis that belimumab, an anti-BAFF monoclonal antibody, may be effective in patients with active GO his currently being tested in a RCT.

Furthermore, an UpToDate review on “Treatment of Graves' orbitopathy (ophthalmopathy)” (Davies and Burch, 2019) does not mention belimumab as a therapeutic option.

Lung Vasculitis

Nasser and Cottin (2020) provided a practical overview of treatment strategies for lung vasculitis associated with ANCAs.  In patients with severe ANCA-associated vasculitis, plasma exchange (PE), as adjunctive therapy to standard treatment, is not associated with improved survival or reduced risk of end-stage kidney disease.  A regimen with reduced dose of glucocorticoids was equally effective to induce remission as a standard regimen.  In patients without organ or life-threatening disease, mycophenolate mofetil can be used in combination with oral glucocorticoid therapy to induce remission, however, with a higher risk of relapse than when using rituximab or cyclophosphamide.  For maintenance of remission, a tailored regimen of rituximab infusion was equivalent to a fixed regimen, with fewer perfusions.  Belimumab did not decrease the relapse rate when added to azathioprine and glucocorticoids.  Avacopan, a complement C5a receptor inhibitor, was effective in replacing high-dose glucocorticoids in achieving complete remission of vasculitis.  The authors concluded that significant advances have been made in the treatment strategy to both induce remission and maintain remission in patients with ANCA-associated vasculitis.  The choice should take into consideration efficacy, cost-effectiveness, safety profile, ease of use, and possibility of individual tailoring of treatment.

Lupus Nephritis

Margiotta and colleagues (2018) stated that the treatment of lupus nephritis (LN) is an unmet need in the management of patients with SLE.  These investigators reported 2 cases of women affected by LN (Society of Nephrology/Renal Pathology Society (ISN/RPS) Class IV) with serological active disease, high disease activity and marked fatigue.  In both cases, MMF, as induction therapy, was poorly tolerated because of gastro-intestinal (GI) toxicity.  Belimumab, together with low-doses of MMF, was effective as induction treatment leading to early achievement of complete renal response in these 2 selected cases of LN.  The authors also presented a literature review concerning the safety and efficacy of belimumab in LN.  They stated that further studies are needed to evaluate the use of belimumab to manage the renal involvement in patients with SLE.

In December 2020, the U.S. FDA approved Benlysta (belimumab) for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. FDA approval was based on positive results of the BLISS-LN (Efficacy and Safety of Belimumab in Adult Patients with Active Lupus Nephritis) study. BLISS-LN is a randomized, double-blind, placebo-controlled, phase 3, 104-week trial that evaluated the safety and effectiveness of belimumab in 448 patients with active proliferative and/or membranous lupus nephritis. The patients had a clinical diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven lupus nephritis Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with

1. mycophenolate for induction followed by mycophenolate for maintenance, or
2. cyclophosphamide for induction followed by azathioprine for maintenance.

Patients were administered belimumab 10 mg/kg intravenously over 1 hour on Days 0, 14, 28, and then every 28 days plus standard therapy. The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104, defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urine protein:creatinine ratio (uPCR) ≤0.7 g/g and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² or no decrease in eGFR of >20% from pre-flare value. The secondary endpoints included complete renal response (CRR), defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: uPCR <0.5 g/g and eGFR ≥90 mL/min/1.73 m² or no decrease in eGFR of >10% from pre-flare value, PERR at Week 52, and Time to Renal-Related Event or Death. The study met its primary endpoint demonstrating that a statistically significant greater number of patients achieved PERR at two years (or 104 weeks) when treated with belimumab plus standard therapy compared to placebo plus standard therapy in adults with active LN (43% vs 32%, odds ratio (95% CI) 1.55 (1.04, 2.32), p=0.0311). Statistical significance compared to placebo across all four major secondary endpoints was achieved, including CRR and Time to Renal-Related Event or Death. The safety results are consistent with the known safety profile of belimumab (GSK, 2020a, GSK 2020b).

Myasthenia Gravis

Diaz-Manera et al (2012) stated that new treatments for immune mediated diseases have increased notably in the last 10 years.  Monoclonal antibodies directed against different components of the immune system have appeared, along with new drugs from the hematology field.  In the case of myasthenia gravis (MG), many of these new treatments have been used in experimental animal models and also in patients.  These investigators reviewed the progress in the field of MG treatment achieved in the last 5 years.  Firstly, the current treatment protocol was introduced.  Secondly, new data from recent randomized trials and case series of patients treated with methotrexate, cyclophosphamide, rituximab or improved systems of apheresis was reported.  Finally, all future treatments that are currently under evaluation in pre-clinical animal models of experimental autoimmune MG were discussed.  Evidence supporting the use of methotrexate and rituximab in MG has been published recently, in addition to conflicting randomized trials that were not successful, evaluating the use of tacrolimus as a steroid sparing agent.  New promising therapies (e.g., belimumab and eculizumab) are currently under evaluation in clinical trials.

In a phase-II, multi-center, placebo-controlled, double-blind study, Hewett and colleagues (2018) examined the safety and efficacy of belimumab in patients with generalized MG who remained symptomatic despite standard of care (SoC) therapy.  Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo.  Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period.  The primary efficacy end-point was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs.  A total of 40 subjects were randomized (placebo n = 22; belimumab n = 18).  The mean change in QMG score from baseline at week 24 was not significantly different for belimumab versus placebo (p = 0.256).  There were no statistically significant differences between treatment groups for secondary end-points, including the MG Composite and MG-Activity of Daily Living scores.  Acetylcholine receptor antibody levels decreased over time in both treatment groups.  No unexpected AEs were identified and occurrence was similar in the belimumab (78 %) and placebo (91 %) groups; 1 subject receiving placebo died (severe sepsis) during the treatment phase.  The authors concluded that the primary end-point was not met for belimumab in participants with generalized MG receiving SoC.  There was no significant difference in mean change in the QMG score at week 24 for belimumab versus placebo. The safety profile of belimumab was consistent with previous SLE studies.  This study provided Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo.

Primary Membranous Nephropathy

Barrett and colleagues (2020) noted that immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities.  In a prospective, open-label, experimental study, these researchers examined the effect of belimumab on proteinuria and PLA2R-Ab in patients with PMN.  A total of 14 subjects with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks).  Changes in proteinuria (urinary protein/creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analyzed during treatment and up to 6 months following treatment.  A total of 11 subjects completed to the primary end-point (week 28) and 9 subjects completed the study.  In the ITT population, baseline proteinuria of 724 mg/mmol [95% CI: 579 to 906] decreased to 498 mg/mmol (95 % CI: 383 to 649) and 130 mg/mmol (95 % CI: 54 to 312) at weeks 28 and 104, respectively, with changes statistically significant from week 36 (n = 11, p = 0.047).  PLA2R-Ab decreased from 174 RU/ml (95 % CI: 79 to 384) at baseline to 46 RU/ml (95 % CI: 16 to 132) and 4 RU/ml (95 % CI: 2 to 6) at weeks 28 and 104, respectively, becoming statistically significant by week 12 (n = 13, p = 0.02); 9 subjects achieved partial (n = 8) or complete (n = 1) remission.  Subjects with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up; AEs were consistent with those expected in this population.  The authors concluded that belimumab treatment in patients with PMN could reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.  These researchers stated that these findings are supportive of further study with belimumab in PMN, either alone or in combination with other therapies.

Furthermore, an UpToDate review on “Treatment of idiopathic membranous nephropathy” (Cattran, 2019) does not mention belimumab as a therapeutic option.

Renal Vasculitis

Walters and colleagues (2020) noted that renal vasculitis presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterized by acute kidney injury (AKI), hematuria and proteinuria.  Treatment of these conditions involve the use of steroid and non-steroid agents in combination with PE.  Although immunosuppression overall has been very successful in the treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy, the use of PE and the role of new therapies. This 2019 publication is an update of a review first published in 2008 and updated in 2015.  In this updated Cochrane review, these researchers examined the benefits and harms of any intervention used for the treatment of renal vasculitis in adults.  They searched the Cochrane Kidney and Transplant Register of Studies up to November 21, 2019 through contact with the Information Specialist using search terms relevant to this review.  Studies in the Register are identified through searches of CENTRAL, Medline, and Embase, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov; RCTs examining any intervention for the treatment of renal vasculitis in adults were selected for analysis; 2 authors independently assessed study quality and extracted data.  Statistical analyses were performed using a random effects model and results expressed as RR with 95 % CI for dichotomous outcomes or MD for continuous outcomes.  A total of 40 studies (3,764 patients) were included.  Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers.  Later studies tend to have improved in all areas of quality, aided by the development of large international study groups.  Induction therapy: PE as adjunctive therapy may reduce the need for dialysis at 3 (2 studies: RR 0.43, 95 % CI: 0.23 to 0.78; I2 = 0 %) and 12 months (6 studies: RR 0.45, 95 % CI: 0.29 to 0.72; I2 = 0 %) (low certainty evidence); PE may make little or no difference to death, serum creatinine (SCr), sustained remission or to serious or the total number of AEs; PE may increase the number of serious infections (5 studies: RR 1.26, 95 % CI: 1.03 to 1.54; I2 = 0 %; low certainty evidence).  Remission rates for pulse versus continuous CPA were equivalent but pulse treatment may increase the risk of relapse (4 studies: RR 1.79, 95 % CI: 1.11 to 2.87; I2 = 0 %) (low certainty evidence) compared with continuous cyclophosphamide.  Pulse CPA may make little or no difference to death at final follow-up, or SCr at any time-point.  More patients required dialysis in the pulse CPA group.  Leukopenia was less common with pulse treatment; however, nausea was more common.  Rituximab compared to CPA probably made little or no difference to death, remission, relapse, serious infections, or severe AEs.  Kidney function and dialysis were not reported.  A single study reported no difference in the number of deaths, need for dialysis, or AEs between mycophenolate mofetil (MMF) and CPA.  Remission was reported to improve with MMF however more patients relapsed.  A lower dose of steroids was probably as effective as high dose and may be safer, causing fewer infections; kidney function and relapse were not reported.  There was little of no difference in death or remission between 6 and 12 pulses of CPA.  There was low certainty evidence that there were less relapses with 12 pulses (2 studies: RR 1.57, 95 % CI: 0.96 to 2.56; I2 = 0 %), but more infections (2 studies: RR 0.79, 95 % CI: 0.36 to 1.72; I2 = 45 %); 1 study reported severe AEs were less in patients receiving 6 compared to 12 pulses of CPA.  Kidney function and dialysis were not reported.  There was limited evidence from single studies regarding the effectiveness of IVIG, avacopan, methotrexate, immunoadsorption, lymphocytapheresis, or etanercept.  Maintenance therapy: Azathioprine (AZA) has equivalent efficacy as a maintenance agent to CPA with fewer episodes of leucopenia.  MMF resulted in a higher relapse rate when tested against AZA in remission maintenance.  Rituximab was an effective remission induction and maintenance agent.  Oral co-trimoxazole did not reduce relapses in granulomatosis with polyangiitis.  There were fewer relapses but more serious AEs with leflunomide compared to methotrexate.  There was limited evidence from single studies regarding the effectiveness of methotrexate versus CPA or AZA, cyclosporin versus CPA, extended versus standard AZA, and belimumab.  The authors concluded that PE was effective in patients with severe AKI secondary to vasculitis.  Pulse CPA may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose.  While CPA is standard induction treatment, rituximab and MMF were also effective; and AZA, methotrexate as well as leflunomide were effective as maintenance therapy.  These researchers stated that further studies are needed to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Retinal Vasculitis

De Scheerder and colleagues (2016) reported the case of a 26-year old African female who was treated successfully with belimumab in a case of severe membranous lupus nephritis and retinal vasculitis, resistant to 1st line therapy.  She presented initially with chronic dacryoadenitis and screening showed nephrotic-range proteinuria.  Biopsy of the kidney confirmed the diagnosis of membranous lupus nephritis.  Clinical features (joint pain, dacryoadenitis, retinal vasculitis and lupus nephritis) in combination with serology (positive anti-double-stranded DNA (ds-DNA) antibodies, hypocomplementemia) confirmed the diagnosis of SLE.  Treatment was immediately initiated with glucocorticosteroids (GCS), mycophenolate mofetil (MMF) and hydroxychloroquine sulphate (Plaquenil).  Tacrolimus was associated but no effect was observed with the proteinuria remaining in the nephrotic range and secondary effects of the glucocorticoids becoming a real concern.  The patient was started on add-on belimumab with quasi-immediate effect on the proteinuria, making it possible to decrease the dosage of the other immunosuppressants and gradually stop them, even the GCS.  The patient is currently in complete remission after 3 years of treatment with belimumab.  The authors were able to stop immunosuppressive treatment but kept the patient on anti-malarial treatment as the most recent guidelines in treatment of SLE recommend.  This was a single-case study; its findings need to be validated by well-designed studies.

Rhupus

Castillo Dayer and colleagues (2019) noted that patients with rhupus characteristically exhibit symmetric polyarthritis and clinical manifestations suggestive of SLE (malar rash, photosensitivity, hematological manifestations, serositis, and/or skin involvement) and positive anti-dsDNA.  Treatment is unclear and it can include disease-modifying rheumatic drugs like hydroxyl chloroquine, or methotrexate or, in refractory cases, rituximab or abatacept.  These investigators reported a case of 31-year old woman who present with rhupus with skin acute lesions treated with belimumab.  This was the 1st case of rhupus treated with belimumab described in the literature.

An UpToDate review on “Clinical manifestations of mixed connective tissue disease” (Bennett, 2019) states that “A similar overlap between SLE and RA has been called "rhupus".  It is rare, with an estimated prevalence rate of 0.09 %.  Rhupus is characterized by a symmetric erosive polyarthritis of the small and large joints and symptoms of SLE with high titers of antibodies to double-stranded (dsDNA) and Sm as well as RF and anti-CCP antibodies.  Rhupus differs from of MCTD in having only mild systemic involvement, and the presence of Raynaud phenomenon is less common”.  Moreover, this review does not mention belimumab as a therapeutic option.

Sjogren's Syndrome

Mariette et al (2015) evaluated the safety and effectiveness of belimumab in patients with primary Sjogren's syndrome (pSS).  Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjogren's syndrome A-positive and had current systemic complications or salivary gland enlargement, or early disease (less than 5 years), or biomarkers of B cell activation.  They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24.  The primary end-point, assessed at week 28, was improvement in 2 of 5 items: reduction in greater than or equal to 30 % in dryness score on a visual analog scale (VAS), greater than or equal to 30 % in fatigue VAS score, greater than or equal to 30 % in VAS pain score, greater than or equal to 30 % in systemic activity VAS assessed by the physician and/or greater than 25 % improvement in any B cell activation biomarker values.  Among 30 patients included, the primary end-point was achieved in 18 (60 %).  The mean (SD) European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p = 0.0015) and EULAR) Sjogren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p = 0.0174).  The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p = 0.0021), 6.9 (1.8) to 6.0 (2.2) (p = 0.0606) and 4.6 (2.6) to 4.7 (2.4) (p = 0.89), respectively.  Salivary flow and Schirmer's test did not change.  The authors concluded that these encouraging results justified future randomized controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment.

In a systematic review and meta-analysis, Letaief and colleagues (2018) examined the clinical safety and effectiveness of B-cell targeted therapies for pSS.  These investigators performed a systematic literature review using databases including Medline, Embase and Cochrane.  Only articles reporting controlled or prospective studies of biological disease-modifying anti-rheumatic drugs (b-DMARDs) modulating B cells in treatment of pSS were selected.  The highest-quality studies were selected for meta-analysis.  The primary outcome of interest was clinical efficacy at week 24 on fatigue, dryness, Schirmer test, salivary flow rate and the full EULAR Sjogren's syndrome disease activity index (ESSDAI) score including biological domain.  For the efficacy criteria used, the difference between rituximab and placebo groups was expressed as mean difference (MD).  A total of 18 articles (13 of rituximab, 3 of belimumab, 1 of epratuzumab and 1 of baminercept) were identified for detailed evaluation; 4 randomized controlled trials (RCTs) of rituximab treatment versus placebo involving 300 patients were included for quantitative analysis.  No significant differences were observed between groups in the meta-analysis of mean improvements between baseline and week 24 in fatigue VAS [MD -3,24 95 % CI: -30,21 to 23.72], oral dryness VAS [MD -8.41 95 % CI: -35.06 to 18.24], salivary flow rate [MD 0.04 95 % CI: -0.03 to 0.11] and Schirmer test [MD 0.35 95 % CI: -2.13 to 2.82)].  Rituximab was relatively safe compared to placebo.  The authors concluded that the findings of this review showed that rituximab is not effective in pSS with the designs and outcomes proposed in the trials; RCTs are needed to prove the effectiveness of belimumab and epratuzumab in this indication.  The RCT evaluating baminercept failed to achieve its primary end-point.

According to the European League Against Rheumatism (EULAR)’s recommendations for the management of Sjogren's syndrome (SjS) (Ramos-Casals et al, 2020), “Some promising results recently reported in small open-label studies testing biologics (belimumab, anakinra) must be confirmed in further large well-designed RCTs, while advance results of a large trial in primary SjS do not indicate a clinical benefit of abatacept”. 

In a systematic review, Alvarez-Rivas and colleagues (2020) examined the safety and efficacy of belimumab in patients with pSS.  The search included manuscripts evaluating the safety or efficacy of belimumab in patients with pSS (American-European Consensus Criteria 2002) published between 2004 and 2017 in Medline, Embase or Cochrane databases; 2 reviewers independently selected the articles, extracted data and examined the quality of the evidence following Scottish Intercollegiate Guidelines Network (SIGN) recommendation grades.  Out of 135 citations, only 3 articles were included.  All of them publishing results from the same study at different time-points including 28 patients.  At week 28, improvement was observed for VAS dryness score and glandular manifestations in 37 % and 77 % of patients, respectively, which persisted at week 52 (W52).  Belimumab was well-tolerated and safely administered.  The authors concluded that published evidence to determine the efficacy of belimumab in pSS is limited.

Systemic Sclerosis

Katsiar and colleagues (2018) noted that systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, immune activation, and extensive collagen deposition.  Microvasculopathy and immune activation occur very early in the disease process.  Evidence from animal models and in-vitro studies indicated that T-cells and B-cells activate fibroblasts to produce collagen.  Traditional immuno-suppressants, cyclophosphamide(CyP), methotrexate(MTX), and more recently mycophenolate mofetil (MMF), may prove more effective if used very early in the disease course.  These drugs showed some benefit in skin (MTX, CyP, MMF) and lung function (CyP, MMF).  Biologicals, such as intravenous immunoglobulin (IVIG), belimumab (Beli), tocilizumab(TCZ), abatacept (Aba), rituximab (RTX) and fresolimumab (Fresu) appeared promising as they exhibited some benefit in skin (IVIG, Beli, TCZ, Aba, RTX, Fresu), hand function (IVIG), and joints (IVIG, TCZ, Aba).  Autologous stem cell transplantation showed the best therapeutic efficacy on skin and internal organs, and looks very promising, as modification of transplantation immunosuppression is decreasing the early high mortality.

Wegener's Granulomatosis (Granulomatosis with Polyangiitis)

Alesaeidi and colleagues (2020) stated that Wegener's granulomatosis, also known as granulomatosis with polyangiitis (GPA), is a rare and systemic autoimmune disease, causing necrotizing vasculitis of small arteries and veins.  The majority of diagnosed patients with GPA have circulating ANCA directed against proteinase 3 (PR3).  These researchers examined the last findings and uncertainties regarding treatments of GPA.  Between the available treatments in addition to corticosteroids, cyclophosphamide (CYP) is effective for remission-induction, while it is associated with some serious side effects, such as infertility and increased risk of malignancies.  On the other hand, rituximab (RTX) appeared a safer alternative option and as effective as CYP.  It could be used as both remission-induction and maintenance therapy in GPA patients, especially in women of child-bearing age.  Pregnant patients, who must not be exposed to the CYP and RTX could be well-managed with IVIG.  Co-trimoxazole, which is widely used to treat certain bacterial infections or as prophylaxis in immunosuppressed patients could be effective in preventing disease relapse.  In the meantime, 15-deoxyspergualin, PE are other therapeutic options with a low level of evidence.  Regarding potential treatments, ofatumumab, ocrelizumab, belimumab, atacicept, tabalumab, abatacept (CTLA4-Ig), and Janus kinase inhibitors appeared to be effective.  Renal involvement, older age, the presence of baseline organ damage, delayed-diagnosis of disease, rising in creatinine level, and higher neutrophil/lymphocyte ratio was associated with poor outcomes.  The authors stated that optimum doses of medications, prediction of therapeutic response and disease relapse, explaining lack of response in some patients, treating children with GPA, and management of GPA during the pregnancy are controversial issues, which need further studies. 

An UpToDate review on “Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease” (Falk and Merkel, 2020) does not mention belimumab as a therapeutic option.  Furthermore, an UpToDate review on “Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy” (Merkel et al, 2020) lists belimumab as an investigational agent.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0490	Injection, Belimumab, 10 mg
Other HCPCS codes related to the CPB:
J0390	Injection, chloroquine hydrochloride
J0456	Injection, azithromycin, 500 mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphaste, 1 mg
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J7312	Injection, dexamethasone, intravitreal implant, 0.1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7502	Cyclosporine, oral, 100 mg
J7509	Methylprednisolone oral, per 4 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Cyclosporine, parenteral, 250 mg
J7517	Mycophenolate mofetil, oral, 250 mg
J7637	Dexamethasone, inhalation solution, compounded product, administered through dme, concentrated form, per milligram
J7638	Dexamethasone, inhalation solution, compounded product, administered through dme, unit dose form, per milligram
J8540	Dexamethasone, oral 0.25 mg
J8610	Methotrexate; oral, 0.25 mg
J9070	Cyclophosphamide, 100 mg [not covered when used in combination with Benlysta]
J9311	Injection, rituximab 10 mg and hyaluronidase
J9312	Injection, rituximab, 10 mg
Q0144	Azithromycin dihydrate, oral, capsules/powder, 1 gram
Q5115	Injection, rituximab-abbs, biosimilar, (Truxima), 10 mg
Q5119	Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg
Q5123	Injection, rituximab-arrx, biosimilar, (riabni), 10 mg
ICD-10 codes covered if selection criteria are met:
M32.0 - M32.9	Systemic lupus erythematosus (SLE)
ICD-10 codes not covered for indications listed in the CPB :
C88.0	Waldenstrom macroglobulinemia
D68.61	Antiphospholipid syndrome
D69.3	Immune thrombocytopenic purpura
E05.00 - E05.01	Thyrotoxicosis with diffuse goiter [Graves' orbitopathy (ophthalmopathy)]
G35	Multiple sclerosis
G70.00	Myasthenia gravis without (acute) exacerbation
H20.00 - H21.9	Disorders of iris and ciliary body
H35.061 - H35.069	Retinal vasculitis
I77.6	Arteritis, unspecified [renal vasculitis]
K75.4	Autoimmune hepatitis
L40.50 - L40.59	Psoriatic arthritis
M05.00 - M06.9	Rheumatoid arthritis
M1A.00x+ - M10.9	Gout
M30.0	Polyarteritis nodosa [antibody-associated vasculitis]
M30.1	Polyarteritis with lung involvement [Churg-Strauss]
M31.30 - M31.31	Wegener's granulomatosis [antibody-associated vasculitis]
M34.0 - M34.9	Systemic sclerosis
M35.00 - M35.09	Sicca syndrome [Sjögren]
N00.2	Acute nephritic syndrome with diffuse membranous glomerulonephritis
N01.2	Rapidly progressive nephritic syndrome with diffuse membranous glomerulonephritis
N02.2	Recurrent and persistent hematuria with diffuse membranous glomerulonephritis
N03.2	Chronic nephritic syndrome with diffuse membranous glomerulonephritis
N04.2	Nephrotic syndrome with diffuse membranous glomerulonephritis
N05.2	Unspecified nephritic syndrome with diffuse membranous glomerulonephritis
N06.2	Isolated proteinuria with diffuse membranous glomerulonephritis
N07.2	Hereditary nephropathy, not elsewhere classified with diffuse membranous glomerulonephritis
N18.4 - N18.6	Chronic kidney disease, stage 4 (severe), stage 5, ESRD
T86.810	Lung transplant rejection [antibody-mediated rejection]
Z94.0	Kidney transplant status
Z94.1	Heart transplant status
Z94.2	Lung transplant status
Z94.3	Heart and lungs transplant status
Z94.4	Liver transplant status
Z94.82	Intestine transplant status
Z94.83	Pancreas transplant status
Z94.84	Stem cells transplant status
Z99.2	Dependence on renal dialysis

The above policy is based on the following references: