Efficacy and safety of bortezomib in refractory lupus nephritis: a single-center experience.

BACKGROUND AND OBJECTIVES: Resistant lupus nephritis (LN) has been associated with the persistence of long-lived plasma cells. Preliminary studies identified bortezomib as a potential treatment option for patients with refractory LN. The aim of this study was to analyze the efficacy and safety of bortezomib in the treatment of severe refractory LN. METHODS: This retrospective study included 12 female patients diagnosed for the first time with class IV or IV/V LN with acute or rapidly progressive kidney injury (n = 11) and/or severe nephrotic syndrome (n = 1) who showed resistance to induction therapy with cyclophosphamide, steroids, mycophenolate, and rituximab, and were treated with either intravenous or subcutaneous bortezomib plus intravenous dexamethasone. RESULTS: All patients with acute or rapidly progressive kidney injury showed a significant reduction in both biochemical and immunological activity after a mean of 6 (minimum 5, maximum 7) weekly cycles of bortezomib regimen, with a significant increase in C3 levels and a significant decrease of anti-ds DNA antibody titers, Systemic Lupus Erythematosus Disease Activity Index score, serum creatinine, and proteinuria. One patient (8.3%) achieved a complete response, and 10 patients (83.4%) achieved a partial response. During follow-up, all these patients maintained partial responses under treatment with mycophenolate and low-dose glucocorticoids. The patient with refractory nephrotic syndrome showed a partial response but relapsed 11 months after the end of bortezomib treatment and was resistant to treatment. A significant decrease in serum IgG levels after initiation of bortezomib treatment was observed in all patients, five of them (41.6%) showed hypogammaglobulinemia (<500 mg/dl), but no patient suffered from opportunistic infections; in only two patients (16.6%) hypogammaglobulinemia persisted at the end of follow-up. Two patients (16.6%) suffered from sensory neuropathy, which led to bortezomib treatment discontinuation. CONCLUSIONS: Bortezomib may be an effective option for refractory LN, but close monitoring must be performed for possible adverse events such as peripheral neuropathy and hypogammaglobulinemia.

Realized heritability of tonic immobility in White Leghorn hens: a replicated single generation test.

Fearfulness was measured as latency to recover from induced tonic immobility using White Leghorn hens from a population originated by crossing three different strains selected for egg number and egg weight. Realized heritability was calculated in a single generation selection experiment with eight replicates, each consisting of 76 40-wk-old females from which 21% were selected for decreased tonic immobility duration. A randomly selected control population was maintained for each replicate. Separately from this experiment, fear differences between ages and sexes were investigated at 1, 2, 4, 8, 12, 16, 20, 24, 28, and 32 wk. The realized heritability (.32 +/- .10) indicates that induced tonic immobility should respond to selection. It was numerically higher than the estimate calculated by half-sib analysis of variance in the base population (.18 +/- .07); the logarithmic transformation did not yield higher heritability estimates. Crossing effects were evaluated in two different crossbreds, i.e., Leghorn x Castellana and Buff Prat x White Prat, which suggested important negative heterotic effects for this fear-related trait (-31% and -54%, respectively). Significant (P < .05) quadratic and cubic variation between 1 and 32 wk of age was obtained in females and males, respectively; the involvement of these age effects make it difficult to generalize about realized heritability for tonic immobility. Tonic immobility increased from 32 to 72 wk. Differences between the sexes were apparent, males showing longer tonic immobility durations than females except in the postjuvenile period before sexual maturity, suggesting a relationship between this trait and hormonal changes.