Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease of unknown cause. It has a broad range of clinical and serological manifestations and can affect many organs. Clinical symptoms of SLE include fatigue, fever, arthralgia, myalgia, changes in weight, skin and mucus membrane lesions and ulcers, and vascular disease. SLE can also include cardiac, renal, pulmonary, and neurologic involvement. Due to its multisystem involvement and likelihood of changes in presentation, the diagnosis of SLE may be difficult.3

The American College of Rheumatology (ACR) recommend referral to a rheumatologist and/or another appropriate specialist to establish the diagnosis of SLE; assess activity and severity level; and management of the disease.4

The 2019 update of the EULAR recommendations for the management of SLE recommend the following6:

•             Hydroxychloroquine is recommended for all patients with SLE, unless contraindicated, at a max dose of 5 mg/kg/real body weight (BW)

•             Glucocorticoids may be used for rapid symptoms relief, but long-term goals should be to minimize daily glucocorticoid dose to ≤7.5 mg/day prednisone equivalent or discontinue

•             Immunosuppressive therapies should be initiated in patients that are not responding to hydroxychloroquine (alone or in combination with glucocorticoids) OR in patients that are unable to reduce the glucocorticoid dose to the recommended maintenance dose

•             Immunosuppressive therapies include methotrexate, azathioprine, or mycophenolate

•             Cyclophosphamide can be used for severe organ or life threatening SLE as well as rescue therapy for those patients that do not respond to other immunosuppressive agents

•             Add on treatment with belimumab should be considered in patients with inadequate response to standard of care therapy (combinations of hydroxychloroquine and glucocorticoids with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses

•             Rituximab may be considered in organ-threatening refractory disease or in those with intolerance/contraindication to standard immunosuppressive agents

HHS notes that the same management strategies apply to children and adolescents with SLE.5

Lupus Nephritis

Lupus nephritis (LN) is a common cause of kidney injury and failure in patients with SLE. Roughly 50% of patients with SLE will develop LN at some point in their SLE disease course and between 10% to 30% of those patients will progress to kidney failure requiring kidney transplant. Mortality in patients with LN is significantly higher than those that do not develop LN, with death occurring in 5% to 25% of patients with proliferative LN. LN typically develops early in SLE disease course and can often be present at initial diagnosis of SLE. LN results due to an accumulation of immune complex in the glomeruli. Intrarenal inflammation occurs leading to permanent damage to the kidney.7

Diagnosis of LN can be challenging, especially if the patient has not been initially diagnosed with SLE. Serum creatinine levels, urine dipstick testing, and urine sediment are necessary tools for LN evaluation. Proteinuria in patients with SLE is suggestive of a diagnosis of LN.6 The American College of Rheumatology (ACR) indicates that all patients with clinical evidence of LN should undergo a renal biopsy to determine disease classification and confirm diagnosis of LN. The ACR also indicates that treatment should be based off of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) LN classification. The ISN/RPS breaks down LN into the following 6 classes9:

•             Class I: minimal mesangial lupus nephritis

•             Class II: mesangial proliferative lupus nephritis 

•             Class III: focal lupus nephritis

•             Class IV: diffuse lupus nephritis

•             Class V: membranous lupus nephritis

•             Class VI: advanced sclerotic lupus nephritis

The ACR recommends the following for the treatment of lupus nephritis8:

•             Class I and II: do not usually require immunosuppressive treatment

•             Class III and IV, Class V when combined with class III or IV: require aggressive therapy with glucocorticoids and immunosuppressive agents

•             Class V alone or Class VI: prepare for kidney transplant

•             Induction therapy for class III, IV, and V when combined with class III or IV should consist of mycophenolate mofetil (MMF) or IV cyclophosphamide plus glucocorticoids for 6 months

•             Improvement after 6 months of induction therapy: recommendation is to switch patients to MMF or azathioprine (AZA) with or without glucocorticoids for maintenance therapy

•             No improvement after 6 months of induction therapy:

o            Switch the patient to the other induction agent in combination with glucocorticoids for another 6 months

o            If improvement is seen after 6 months, switch to maintenance therapy noted above

o            If no improvement after 6 months, switch to rituximab or calcineurin inhibitors in combination with glucocorticoids

Benlysta SLE Clinical Trials¹

The safety and efficacy of belimumab was evaluated in two randomized, double-blind, placebo-controlled, phase III studies involving patients age 18 and older with SLE (BLISS-52 and BLISS-76 study). The design of these studies was based on the results of a phase II study which identified that patients who were autoantibody-positive had a better response to belimumab. As a result, BLISS-52 and BLISS-76 limited the study population to only include autoantibody-positive SLE patients. Patients were on a standard of care SLE treatment regimen comprising of at least one of the following: corticosteroids, antimalarials, nonsteroidal anti-inflammatory drugs (NSAIDS), and/or immunosuppressives (azathioprine, methotrexate, or mycophenolate). Patients with severe active lupus nephritis and severe central nervous system (CNS) lupus were excluded. Patients using other biologics including B-cell targeted therapies such as rituximab or intravenous cyclophosphamide in the previous six months were also excluded.

BLISS-52 (N=865) and BLISS-76 (N=826) had similar designs with the exception of duration. BLISS-76 was 76 weeks in duration and BLISS-52 was 52 weeks in length. Eligible patients had active SLE disease which was defined as a Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score >6. Patients were randomly assigned to receive belimumab 1 mg/kg, 10 mg/kg, or placebo in addition to standard of care. The study medication was administered on Days 0, 14, 28, and then every 28 days for 48 weeks in BLISS-52 and 72 weeks in BLISS-76.

In both BLISS-52 and BLISS-76, the proportion of SLE patients achieving a SLE Responder Index-4 (SRI-4) response was significantly higher in the belimumab 10 mg/kg group than placebo while the effect on SRI-4 was not consistently significantly different for the belimumab 1 mg/kg group.

The safety and efficacy of Benlysta in pediatric patients was evaluated in an international, randomized, double-blind, placebo-controlled, 52-week study conducted in 93 patients with a clinical diagnosis of SLE according to the ACR classification criteria. Patients had a SELENA-SLEDAI score >6 and positive autoantibodies at screening. Patients were on stable SLE treatment regimen and had similar inclusion and exclusion criteria as in the adult studies. The primary endpoint was the same as the adult trials, and there was a numerically higher proportion of pediatric patients achieving a response in SRI-4 and its components in patients receiving Benlysta plus standard therapy compared with placebo plus standard therapy (53% vs 44%, odds ratio 1.49 [CI 0.64, 3.46]).

Saphnelo SLE Clinical Trials²

The safety and efficacy of anifrolumab-fnia were evaluated in three 52-week treatment period 52-week treatment period, multicenter, randomized, double-blind, placebo-controlled studies (Trial 1 [NCT01438489], Trial 2 [NCT02446912] and Trial 3 [NCT02446899]). Patients were diagnosed with SLE according to the American College of Rheumatology (1982 revised) classification criteria. All patients were ≥18 years of age and had moderate to severe disease, with a SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥6 points, organ level involvement based on BILAG assessment, and a Physician’s Global Assessment [PGA] score ≥1, despite receiving standard SLE therapy consisting of either one or any combination of oral corticosteroids (OCS), antimalarials and/or immunosuppressants at baseline. Patients continued to receive their existing SLE therapy at stable doses during the clinical trials, with the exception of OCS (prednisone or equivalent) where tapering was a component of the protocol. Patients who had severe active lupus nephritis and patients who had severe active central nervous system lupus were excluded. The use of other biologic agents and cyclophosphamide were not permitted during the trials; patients receiving other biologic therapies were required to complete a wash-out period of at least 5 half-lives prior to enrollment. Patients received anifrolumab-fnia or placebo, administered by intravenous infusion, every 4 weeks.

Efficacy of SAPHNELO was established based on assessment of clinical response using the composite endpoints, the British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) and the SLE Responder Index (SRI-4). Trial 1 primary endpoint was a combined assessment of the SRI-4 and the sustained reduction in OCS (<10 mg/day and ≤OCS dose at week 1, sustained for 12 weeks) measured at Week 24. Trial 2 and 3 were similar in design. Trial 2 randomized 457 patients who received anifrolumab-fnia 150 mg, 300 mg or placebo (1:2:2). Trial 3 randomized 362 patients (1:1) who received anifrolumab-fnia 300 mg or placebo. The primary endpoints were improvement in disease activity evaluated at 52 weeks, measured by SRI-4 in Trial 2 and BICLA in Trial 3 (defined above). Both studies evaluated the efficacy of anifrolumab-fnia 300 mg versus placebo; a dose of 150 mg was also evaluated for dose-response in Trial 2. The reduction in disease activity seen in the BICLA and SRI-4 was related primarily to improvement in the mucocutaneous and musculoskeletal organ systems. Flare rate was reduced in patients receiving SAPHNELO compared to patients who received placebo although the difference was not statistically significant.

BICLA was the primary endpoint in Trial 3; anifrolumab-fnia 300 mg demonstrated statistically significant and clinically meaningful efficacy in overall disease activity compared with placebo, with greater improvements in all components of the composite endpoint. In Trial 3, examination of subgroups by age, race, gender, ethnicity, disease severity [SLEDAI-2K at baseline], and baseline OCS use did not identify differences in response to anifrolumab-fnia.

SRI-4 was the primary endpoint in Trial 2; treatment with anifrolumab-fnia did not result in statistically significant improvements over placebo. In Trials 1 and 3, SRI-4 was a pre-specified analysis. The SRI-4 results are presented in Table 4.

In Trial 3, among the 47% of patients with a baseline OCS use ≥10 mg/day, anifrolumab-fnia demonstrated a statistically significant difference in the proportion of patients able to reduce OCS use by at least 25% to ≤7.5 mg/day at Week 40 and maintain the reduction through Week 52 (p-value = 0.004); 52% (45/87) of patients in the anifrolumab-fnia group versus 30% (25/83) in the placebo achieved this level of steroid reduction (difference 21% [95% CI 6.8, 35.7]). Consistent trends in favor of anifrolumab-fnia compared to placebo, on effect of reduction of OCS use, were observed in Trial 1 and 2, but the difference was not statistically significant.

Benlysta LN Clinical Trials¹

The safety and efficacy of Benlysta in patients with lupus nephritis was evaluated in a 104 week, randomized, double-blind, placebo controlled trial that included 448 patients with active proliferative and/or membranous lupus nephritis. Patients had to be at least 18 years of age and ANA positive SLE that fulfilled the ACR classification criteria. Patients were required to have a urine protein to creatinine ratio of 1 or more and biopsy-proven lupus nephritis ISN/RPS class III, IV, or V. Induction therapy had to be initiated within 60 days before randomization and therapies had to include either induction with glucocorticoids in combination with MMF or IV cyclophosphamide, followed by MMF or AZA for maintenance 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 major 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 (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined by quantified increase in proteinuria and/or impaired renal function], or receipt of renal disease-related prohibited therapy due to inadequate lupus nephritis control or renal flare management).

The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving Benlysta plus standard therapy compared with placebo plus standard therapy (43% vs 32%, p=0.031). The subgroup analysis of PERR and CRR by biopsy class indicated the odds ratios for patients with class 5 without combined class III or class IV favored placebo plus standard therapy over Benlysta plus standard therapy. The odds ratio for all other classes or combinations favored Benlysta plus standard therapy. Most of the secondary endpoint were statistically significant (CRR at week 100 p=0.017 [30% vs 20% Benlysta vs placebo], PERR at week 52 p=0.025 [47% vs 35% Benlysta vs placebo]).

Safety¹

Benlysta is contraindicated in patients that have experienced anaphylaxis with belimumab.¹ 

Saphnelo is contraindicated in patients with a history of anaphylaxis with anifrolumab-fnia.²

Saphnelo is not recommended in combination with other biologic therapies.²

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