Abatacept and Mycophenolate Mofetil Combination Therapy in Refractory Pediatric Systemic Lupus Erythematosus: A Case Series

Rhina D. Castillo 0 1 2 Suhas M. Radhakrishna 0 1 2 Andreas O. Reiff 0 1 2 Colleen Azen 0 1 2 Katherine A. B. Marzan 0 1 2 0 C. Azen Biostatistics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California , Los Angeles, CA, USA 1 S. M. Radhakrishna Division of Rheumatology, Kaiser Permanente Medical Group , Oakland, CA, USA 2 R. D. Castillo (&) A. O. Reiff K. A. B. Marzan Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California , Los Angeles, CA, USA Introduction: Lupus nephritis (LN) in pediatric systemic lupus erythematosus (pSLE) requires treatment with corticosteroids (CS) and mycophenolate mofetil (MMF) or cyclophosphamide (CYC). However, some patients fail standard therapy leaving physicians with few options. Although two recent phase II/III randomized controlled trials using abatacept (ABA) with and without MMF in adult SLE did not meet their endpoints, we examined if this combination therapy may have a therapeutic benefit in pSLE patients with refractory class IV and V LN. Methods: We performed a retrospective chart analysis of five pSLE patients with class IV and V LN. All patients were treated with ABA ? MMF after previous failure to CYC and MMF. CS doses and SLE Disease Activity Index (SLEDAI) score were assessed at diagnosis and after 12 and 24 weeks of each treatment. Results: Patient age at diagnosis was 9-15 years (mean 12.6 2.3). Average disease duration before initiation of ABA ? MMF therapy was 22-97 months (mo) (mean 52.8 30.8). Treatment with ABA ? MMF resulted in an improvement in SLEDAI score and reduction in CS dose by 12 weeks in all five patients. One patient achieved complete remission and three patients were weaned off steroids after 7-20 mo (mean 13 6.5). Repeated measures analysis of variance showed significant change from SLEDAI at time of diagnosis (baseline) over 24 weeks of treatment with CYC (P = 0.0013) and with ABA ? MMF (P\0.0001). Paired comparison to baseline SLEDAI scores showed some decrease after 12 weeks of treatment with MMF monotherapy (P = 0.0520). - Conclusion: The data suggest that combination therapy with ABA ? MMF may be an alternative option in refractory pSLE nephritis. Additional studies are needed in pSLE to further assess the efficacy of this combination treatment. INTRODUCTION Pediatric systemic lupus erythematosus (pSLE) with class IV/V lupus nephritis (LN) often requires treatment with corticosteroids (CS) and other agents such as azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or cyclophosphamide (CYC) [1, 2]. Although the 5-year survival rate exceeds 95%, the disease may remain intractable in some children [3] and new treatment modalities must sometimes be explored. Abatacept (ABA) is a recombinant fusion protein that acts by competing with CD28 for binding to CD80/CD86, and inhibits its engagement on T cells and plasma cells [4]. Because both T and B cells play an active role in SLE, it was postulated that ABA could be beneficial in SLE. Several studies in murine models of SLE have shown improvement in both SLE and nephritis activity either with CTLA-4Ig alone or in combination with CYC [5, 6]. Although recent controlled trials of ABA, with and without combination treatment with MMF for adult SLE, did not meet their primary or secondary endpoints, exploratory analyses suggested efficacy in some subgroups [7, 8]. ABA is currently FDA approved for treatment of juvenile idiopathic arthritis (JIA) and rheumatoid arthritis, however, its use in pSLE has not been reported [9]. This small case series examines ABA in conjunction with MMF as a potentially effective treatment for pSLE in a subset of children who have failed other medications. MATERIALS AND METHODS We performed a retrospective analysis of children with pSLE, with class IV and V LN diagnosed by pathology at Childrens Hospital Los Angeles, Los Angeles, CA, USA. Patients met at least 4 of the 11 American College of Rheumatology (ACR) criteria for a diagnosis of SLE [10]. All patients received and/or failed treatment with CYC at a daily oral dose of 2 mg/ kg/dose, bi-weekly dose infusion of 10 mg/kg/ dose or monthly infusion of 1,000 mg/m2, MMF monotherapy at a dose of 6001,000 mg/m2/ dose given twice daily (bid) or rituximab (RTX) 750 mg/m2 two doses given 2 weeks apart. Some patients received additional therapeutic interventions with azathioprine (AZA) and cyclosporine (CSA). After an inadequate response to the above therapy, combination therapy with ABA and MMF (ABA ? MMF) was started. Using the SLEDAI scoring system which assigns an index score based on the presence or absence of 24 abnormalities associated with SLE (in 9 organ systems) with scores assigned as follows; 8 for central nervous system involvement and vasculitis, 4 for renal disease and musculoskeletal, 2 for serosal, dermal and immunologic and 1 for constitutional and hematologic. The higher the score, the more disease involvement [11]. The analyzed data points were assigned a (SLEDAI) score at time of diagnosis (referred to as baseline) and then 12 and 24 weeks into each treatment. These data points are separated in time by several years in some cases with minimal overlap of RTX or CYC treatment with the combination therapy. All patients received at least 4 doses of ABA (10 mg/ kg/dose every 2 weeks for 3 doses, then every 4 weeks) in addition to CS. Patients with hypogammaglobulinemia also received replacement IVIG at 0.5 g/kg monthly at the discretion of the treating physician. Institutional review board approval and informed consent were obtained as appropriate. All procedures followed were in accordance with the ethics standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Statistical Analysis Data collected included demographics, medications, laboratories, clinical findings, and adverse events. The pattern of change in SLEDAI scores from time of diagnosis, after 12 and 24 weeks of each treatment, was evaluated with repeated measures analysis of variance (ANOVA), for each drug, using SAS/STAT v 9.2 statistical software (SAS institute Inc., SAS Campus Drive, Cary, NC 27513, USA) with P\0.05 considered statistically significant. CASE PRESENTATION Patient 1 is a white male diagnosed with pSLE at age 14 years based on the positive antinuclear antibodies (ANA), double-stranded DNA (dsDNA), antiphospholipid antibodies (APL), glomerulonephritis (GN) (class IV/V), cytopenias, arthritis, vasculitis and malar rash. SLEDAI score at diagnosis was 32 (Fig. 1), and initial steroid dose was 90 mg daily. He had several complications, including pulmonary embolus and hemorrhage, and splenic re30 o c s IA20 D E LS10 Diagnosi1s2wkCY2C4wkCY1C2wkMM2F4w1k2wMkMAFB2A4+wMkMAFBA+MMF Fig. 1 SLEDAI score per patient infarction for which he was on subcutaneous enoxapari (...truncated)