SAFETY AND EFFICACY OF ANIFROLUMAB IN IMMUNE COMPLEX AND APOL-1 ASSOCIATED LUPUS PODOCYTOPATHY

Background : Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can causes multiorgan inflammation and organ damage through both humeral and cell mediated immune pathways1. Lupus nephritis (LN) is a severe and prevalent complication of SLE leading to increased rates of endstage renal disease (ESRD). Patients with Class III or IV lupus nephritis experience high rates of progression to ESRD with up to 45% requiring renal replacement therapy within 15 years2. Increased interferon gene signatures are seen in up to 80% of patients with lupus nephritis and are strongly correlated with the presence of RNA based autoantibodies including Ro, La, Sm and RNP. Lupus podocytopathy (LP) is a specific class of lupus nephritis that is characterized by an absence of immune complexes and commonly associated with nephrotic syndrome from minimal change and FSGS like lesions. The observation that interferons and toll-like receptor agonists have been shown to increase APOL1 expression by up to 200-fold, has raised the question of whether Lupus podocytopathy is linked to APOL-1 gene expression and thus potentially responsive to Anifrolumab and other Interferon blocking agents3. Two previous,  prospective placebo controlled trials of Anifrolumab in Lupus Nephritis demonstrated an increased rate of complete renal remission compared to placebo but did not examine whether expression of APOL-1 genes altered overall responsiveness4. 

     Herein we report on 11 patients with initial renal biopsies confirming ISN class III, IV, III-V or IV-V lupus nephritis of whom 69% evolved into Lupus FSGS Podocytopathy following standard induction immunosuppression and repeat renal biopsy. We now report the safety and overall response rates to 6 months treatment with low dose (300 mg) Anifrolumab.  

Methods: Prospective, open-labeled study of 11 patients with biopsy confirmed Lupus nephritis who had received one or more standard induction immunosuppressive therapy for a minimum of 6 months and continued to have a UP/Cr ration of > 500 mg/gm. At the time of study entry, all patients were maintained on standard of care immunosuppressive therapy and maximally tolerated RAAS inhibition. All patients were maintained on existing treated with low dose (300 mg) Anifrolumab infusions monthly for a minimum of 6 months. Data were reported as Means + SEM.

Study Inclusion Criteria 1) All patient had a diagnosis of Lupus nephritis ISN class III, IV, V or Class VI Lupus associated FSGS; 2) BP < 140/90 on stable, maximum tolerated dose of an ACE /ARB therapy, 3) APOL-1 testing prior to Anifrolumab infusion; 4) Two pre-study first morning void UP/Cr > 500 mg/gm; 5) CKD-Epi eGFR >30 mls/min/1.73M2 4) and on-going treatment with at least one immunosuppressive agent.   

Definitions: A complete response was defined as UP/Cr < 500 mg/gm after 24 months of follow up with a partial response defined as > 50% reduction from pre-study UP/Cr.

Results: Data from this study is presented in Table-1. The addition of intravenous Anifrolumab to standard of care immunosuppressive therapy induced complete renal remission (< 500 mg.gm UP/Cr) in 36% of patients with an additional 36% reaching a partial remission (>50% reduction in UP/Cr. The aggregate change in UP/Cr is listed in Table-1 for Nephrotic and Non-nephrotic patients as well as patients carrying a least one “at-risk” allele for the APOL-1 gene. UP/Cr was significantly reduced (P<0.05) for both nephrotic and non-nephrotic patients. Both APOL-1 negative patients and those with a single at-risk allele demonstrated a reduction in UP/Cr. However, eGFR tended to fall over a mean follow up period of 12 months.