Omalizumab for Lupus

Background: The immune system in systemic lupus erythematosus is characterized by abnormal activation of various cell types, such as T and B lymphocytes, macrophages and dendritic cells and the production of autoantibodies against nuclear antigens. Until recently most of the pathogenic autoantibodies were thought to be IgG antibodies. We have recently shown that Lyn deficient mice develop a lupus nephritis-like disease which is mediated by basophils activated by IgE autoantibodies. Moreover, SLE patients also have elevated serum self reactive IgEs, and activated basophils that express the lymph node homing molecule CD62L and the MHC Class II molecule, HLA-DR; markers that are associated with increased disease activity. Follow up studies confirmed an association of IgE anti-dsDNA antibodies with active SLE using a SLEDAI score of 4 as a cutoff (unpublished). In addition, we have also observed a strong correlation of IgE dsDNA antibodies with hypocomplementemia strongly suggesting that these autoantibodies are serologic markers of immune activation in SLE. Based on these observations we propose that depleting IgE (including IgE autoantibodies) may lead to improvement in SLE by reducing IgE-induced basophil activation. Omalizumab is a humanized IgG1 monoclonal antibody against human IgE. It is approved by the FDA for the treatment of asthma. Omalizumab was shown to effectively deplete circulating IgE and decrease basophil action. In this study we propose to assess the safety of omalizumab in moderately active lupus patients and to assess its effect on circulating IgE autoantibodies and basophil activation. We will also collect preliminary data about its clinical efficacy. Primary Objective: To determine if omalizumab is tolerated in patients with Systemic Lupus Erythematosus. Secondary Objectives: To determine if the use of omalizumab in a subset of SLE patients with mild to moderate disease and elevated IgE autoantibody levels leads to clinical efficacy. Study Population: Adults 18 years or older diagnosed with SLE attending NIAMS outpatient clinic (OP-9) as well as other rheumatology outpatient clinics and private rheumatologist offices around the country with moderately active lupus (SLEDAI 2K score between 4-14). Design: * Active lupus: Assess study eligibility (week -2). * If fulfills the criteria randomize at 2:1 ratio of omalizumab vs. placebo respectively within 2 weeks (week 0). * Omalizumab loading dose (600 mg) or placebo by subcutaneous injection on day 0, followed by omalizumab (300 mg) or placebo by subcutaneous injection every 4 weeks (weeks 4, 8, 12) * Evaluate patients at weeks 2, 4, 8, 12 and 16. Preliminary analysis of the available data will be done when the last subject completed the blinded phase (week 16). * Open label phase: On week 16 subjects who were randomized to the placebo arm originally will receive 600 mg omalizumab by subcutaneous injection whereas those in the omalizumab arm will receive 300 mg omalizumab by subcutaneous injection in a blinded fashion. After that all subjects will receive omalizumab 300 mg by subcutaneous injection every 4 weeks, on weeks 20, 24, 28. * Evaluate patients at weeks 18, 20, 24, 28 * Follow up phase: Subjects will have a follow up evaluation 4 and 8 weeks after the last dose (weeks 32 and 36). * Allow one time intra-muscular injection of methylprednisolone 0.4 0.75 mg/kg for continued disease activity/flare. Outcome Measures Primary Endpoint: Safety of omalizumab in patients with SLE. Secondary Endpoints: Reduced free IgE autoantibody levels: a statistical significant difference in the change in IgE autoantibody levels between the placebo and omalizumab groups at 16 weeks Decreased basophil activation: a statistically significant difference in the change in the proportion of activated basophils between the placebo and omalizumab groups at 16 weeks Reduced IgG autoantibody levels: a statistically significant difference in the change in IgG autoantibody levels between the placebo and omalizumab group at 16 weeks Pharmacodynamics as measured by total and free IgE and FcepsilonR levels with associated PK Clinical efficacy: the difference in clinical responders at 16 weeks. Clinical response will be defined as an improvement in SLEDAI 2K scores of 4 or more without a worsening in PGA (physician s global assessment) This study will provide important preliminary information about the safety and possible effect of IgE depletion in SLE patients. If omalizumab is well tolerated and shows preliminary evidence of efficacy, follow up studies testing its clinical usefulness are planned. This agent is expected to be devoid of the most common toxicities of therapies commonly used in the treatment of SLE, such as myelosuppression, amenorrhea and osteoporosis.