Faculty Bibliography

OBJECTIVE: To evaluate longitudinal patterns of response to standard of care for systemic lupus erythematosus (SLE) in clinical trials and to identify characteristics that differentiate nonresponders from persistent responders. METHODS: Data on 147 patients with moderately to severely active SLE without acute nephritis who were treated with placebo plus standard of care in two 52-week phase II/III trials were obtained from the Collective Data Analysis Initiative of the Lupus Foundation of America. Cross-sectional and longitudinal analyses of British Isles Lupus Assessment Group (BILAG)-based responses (improvement in all baseline A or B scores without new flare) were performed. Baseline characteristics that discriminated persistent responders from nonresponders were identified using logistic regression. RESULTS: Cross-sectional response rates decreased from 46% to 37% between 12 and 52 weeks. The overall rate of complete and sustained response, i.e., response at all visits, was only 14.3% (95% confidence interval 8.6-19.9%). Agreement between response status at 12 weeks and 36-52 weeks was low (kappa = 0.15-0.29), and only 31% of initial 12-week responders maintained response at all subsequent visits. Baseline factors predictive of persistent response to standard of care included fewer organs with active disease, high C3 levels, and type of background therapy. CONCLUSION: Use of sustained rather than landmark response may reduce high placebo response rates in SLE trials that continue aggressive standard of care. Further exploration to assess the power of this end point to improve discrimination between active and placebo arms is indicated. Lack of temporal stability in response highlights a potential weakness with shorter studies. Rates of response to standard of care are affected by the severity of the disease and the aggressiveness of background immunosuppressive treatments.

Background Several studies have evaluated mortality and shortterm morbidity in neonatal lupus (NL), however there is minimaldata on long term outcomes in children exposed to maternalanti-Ro antibodies in utero. A previous pilot study utilising theResearch Registry for Neonatal Lupus (RRNL) raised concernregarding the development of autoimmune disease in childhood, however the numbers evaluated were small and the patientsstudied were young. This study was initiated to ascertain the current prevalence of autoimmune disease in NL children and theirunaffected siblings, and to evaluate whether fetal or maternal factors associated with the development of future autoimmunity.Materials and methods A retrospective cohort of family membersfrom the RRNL were contacted to evaluate for autoimmune disease. Follow-up questionnaires were completed which included35 items describing symptoms and diagnoses associated withautoimmunity in 138 cardiac NL children, 74 cutaneous NL children, and 134 unaffected siblings. Medical records were obtainedand evaluated from the patient's physicians to confirm diagnoses.Maternal diagnosis of systemic lupus and/or Sjogren's syndromeand fetal cardiac disease severity based on a previously describedseverity score were associated with postnatal autoimmune diseases using chi square and Mann-Whitney analyses.Results Seventeen (8.0%) of NL affected children developed anautoimmune disease at the time of follow up (mean age 11.6+/-9.0 years). These included 3 patients with SLE, 1 with JIA, 3with thyroid disease, 5 with psoriasis, 1 with IBD, 1 with uveitis,1 with UAS and 2 with type 1 DM. Six (4.5%) unaffected siblingsdeveloped an autoimmune disease (mean age 10.6+/-7.1 years),which included 1 with JIA, 1 with Sarcoidosis/ITP, 1 with Myasthenia Gravis/Celiac disease, 1 with psoriasis, 1 with UAS and1 with type 1 DM,. There was a significant association ofbetween having an autoimmune disease and having advancedheart block (11.0% vs. 4.2%, p = 0.03) and a trend towards anassociation with cardiac NL disease severity score (4.43+/-4.89 vs.2.58+/-4.24, p = 0.06). Mother's diagnosis of SLE or Sjogren'sdid not associate with the children's development of autoimmunedisease (p = 0.828).Conclusions Fetuses that develop advanced congenital heartblock as a manifestation of NL may be at greater risk for developing autoimmune diseases later in life. This could potentially relateto a genetic component that makes a Ro exposed fetus both moreprone to inflammatory effects of passive immunity and predisposes to future autoimmunity, independent of the mother's rheumatic disease status