A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Objective: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. Methods: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. Results: The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. Conclusions: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy

Cellular Accumulation of L-Cystine in Rat Kidney Cortex In Vivo

Cellular accumulation of L-cystine in rat kidney cortex in vivo has been studied using L-[(35)S]cystine. The L-[(35)S]cystine radioactivity in plasma decreases to less than 10% of the initially calculated value by 15 min. Four (35)S-containing intracellular products of L-cystine metabolism were identified including cystine, cysteine, reduced glutathione, and an as yet unidentified compound. The latter is probably taurine, cysteinesulphinate, or cysteic acid. Cellular accumulation of these products was found to be more rapid in vivo than in vitro. Cellular accumulation of the products of L-cystine metabolism was found to be essentially unchanged in the presence of ureter ligation. Unlabeled L-lysine administered simultaneously with L-[(35)S]cystine, in both the presence and absence or ureter ligation, enhanced the cellular accumulation of intracellular metabolic products of L-[(35)S]cystine. Simultaneous (35)S cellular accumulation and L-cystine clearance studies were performed both in the presence and absence of L-lysine. L-Lysine enhanced cellular accumulation of (35)S-products despite an accompanying increase in L-cystine clearance. The results are interpreted as evidence for a dissociation between cellular accumulation and transepithelial transport. This evidence for independent luminal transport and peritubular cellular accumulation could explain the apparent paradox in the disease cystinuria where there appears to be a luminal transport defect for L-cystine, but no defect for cellular accumulation of L-cystine metabolic products in vitro

Epidemiology of Systemic Sclerosis in a Large US Managed Care Population

Objective.To estimate the incidence and prevalence of systemic sclerosis (SSc) in a large US managed care organization (MCO) database.Methods.Subjects with claims-based evidence of SSc (ICD-9-CM code 710.1x) were identified from a health plan database. Incidence and prevalence for the period 2003–2008 were calculated.Results.The overall age- and sex-adjusted incidence rate (2003–2008) for SSc was 5.6 cases per 100,000 person-years. The annual prevalence of SSc ranged from 13.5 in 2003 to 18.4 (per 100,000) in 2008.Conclusion.This analysis suggests a higher incidence and lower prevalence of SSc in this MCO than those previously reported for the United States.</jats:sec

Annual Medical Costs and Healthcare Resource Use in Patients with Systemic Sclerosis in an Insured Population

Objective.Systemic sclerosis (SSc) is a chronic autoimmune disease. The objective of our study was to estimate the medical costs and healthcare resource use of subjects with SSc in a large US managed care plan.Methods.Subjects at least 18 years of age and with claims-based evidence of SSc (ICD-9-CM code 710.1x) were identified from a health plan database from 2003 through 2008. Subjects were matched to unaffected controls, based on index date, age, sex, geographic region, time on insurance, and comorbidity score. Costs and resource use were identified during the 12-month postindex period. A generalized linear model (GLM) was used to estimate costs, controlling for demographic and clinical characteristics.Results.In this study, 1648 subjects with SSc were matched to 4944 controls. Mean overall annual medical costs were higher among SSc subjects than controls ($17,365 vs$5,508; p &lt; 0.001). A GLM model supported these results. Evidence of lung disease, gastrointestinal bleeding, or renal disease increased costs (all p &lt; 0.001). Compared to controls, significantly higher proportions of SSc subjects had postindex ambulatory visits, emergency department visits, and inpatient hospital stays (all p &lt; 0.001).Conclusion.Our findings suggest that the medical costs and resource use associated with treating SSc are high (compared to matched controls), and as expected, subjects with serious disease complications experience the highest costs.</jats:sec

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study

ObjectivesThe efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).Methods431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.ResultsCompared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.ConclusionsSifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.Trial registration numberNCT01283139; Results.</jats:sec

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study.

ObjectivesThe efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE).Methods431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52.ResultsCompared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment.ConclusionsSifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity.Trial registration numberNCT01283139; Results