John C Davis

University of California, San Francisco, San Francisco, California, United States

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Publications (71)472.05 Total impact

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    ABSTRACT: The objective of this study was to assess the relationship between short-term and long-term treatment effects measured by the American College of Rheumatology (ACR) 50 responses and to assess the feasibility of predicting 6-month efficacy from short-term data. A rheumatoid arthritis (RA) database was constructed from 68 reported trials. We focused on the relationship between 3- and 6-month ACR50 treatment effects and a generalized nonlinear model was developed to quantify the relationship and test the impact of covariates. The ΔACR50 at 6 months strongly correlated with that at 3 months, moderately correlated with that at 2 months, and only weakly correlated with results obtained at <2 months. A scaling factor that reflected the ratio of 6- to 3-month treatment effects was estimated to be 0.997, suggesting that the treatment effects at 3 months are approaching a "plateau". Drug classes, baseline DAS28 and the magnitude of control arm response did not show significant impacts on the scaling factor. This work quantitatively supports the empirical clinical development paradigm of using 3-month efficacy data to predict long-term efficacy and to inform the probability of clinical success based on early efficacy readout. This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2015 · The Journal of Clinical Pharmacology
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    ABSTRACT: Objectives To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE). Methods Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2). Background Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM). Results Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ∼10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups. Conclusions The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores. Trial registration number NCT00962832.
    Full-text · Article · Jun 2015 · Annals of the rheumatic diseases
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    ABSTRACT: Objectives The interferon (IFN) signature (IS) in patients with systemic lupus erythematosus (SLE) includes over 100 genes induced by type I IFN pathway activation. We developed a method to quantify the IS using three genes—the IS metric (ISM)—and characterised the clinical characteristics of patients with SLE with different ISM status from multiple clinical trials. Methods Blood microarray expression data from a training cohort of patients with SLE confirmed the presence of the IS and identified surrogate genes. We assayed these genes in a quantitative PCR (qPCR) assay, yielding an ISM from the IS. The association of ISM status with clinical disease characteristics was assessed in patients with extrarenal lupus and lupus nephritis from four clinical trials. Results Three genes, HERC5, EPSTI and CMPK2, correlated well with the IS (p>0.96), and composed the ISM qPCR assay. Using the 95th centile for healthy control data, patients with SLE from different studies were classified into two ISM subsets—ISM-Low and ISM-High—that are longitudinally stable over 36 weeks. Significant associations were identified between ISM-High status and higher titres of anti-dsDNA antibodies, presence of anti extractable nuclear antigen autoantibodies, elevated serum B cell activating factor of the tumour necrosis factor family (BAFF) levels, and hypocomplementaemia. However, measures of overall clinical disease activity were similar for ISM-High and ISM-Low groups. Conclusions The ISM is an IS biomarker that divides patients with SLE into two subpopulations—ISM-High and ISM-Low—with differing serological manifestations. The ISM does not distinguish between high and low disease activity, but may have utility in identifying patients more likely to respond to treatment(s) targeting IFN-α. Clinicaltrials.gov registration number NCT00962832.
    Full-text · Article · Mar 2015
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    ABSTRACT: Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity-modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Mar 2015 · Journal of Autoimmunity
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    ABSTRACT: IntroductionTumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LT¿) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin-alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LT¿. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).Methods Patients (n =214) with active RA (¿6 swollen and tender joints, C-reactive protein ¿10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.ResultsPateclizumab reduced the DAS28(4)-ESR response (¿1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (¿1.54), while adalimumab (¿2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AE) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.Conclusions Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.Trial registrationClinicalTrials.gov NCT01225393, Registered 18 October 2010.
    Full-text · Article · Oct 2014 · Arthritis Research & Therapy
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    ABSTRACT: To 1) describe the distribution of patient global assessment (PtGA) scores of disease activity in patients with granulomatosis with polyangiitis (GPA; Wegener's), 2) explore the discordance between PtGA scores and physician global assessment (PhGA) scores of disease activity, and 3) explore whether PtGA scores during disease remission are associated with future disease relapse. Data from the Wegener's Granulomatosis Etanercept Trial (WGET) were used. PtGA and PhGA scores were assessed on 100-mm visual analog scales (VAS). Presence of active disease was determined using the Birmingham Vasculitis Activity Score for WG (BVAS/WG), and remission was defined as a BVAS/WG score of 0. Disease relapse was defined as a BVAS/WG score of >0 after remission had been achieved. Discordance between PtGA and PhGA scores was defined as a difference of ≥20 points between the two measures. Mixed linear models were used in longitudinal analysis of PtGA scores. Data were obtained from 180 patients in the WGET cohort, seen at a total of 1,719 study visits. The mean ± SD PtGA and PhGA disease activity scores (on 100-mm VAS) at baseline were 64.2 ± 27.4 and 55.5 ± 23.4, respectively. PtGA-PhGA discordance occurred in 53% of patients at baseline, and this was inversely associated with newly diagnosed disease (as opposed to relapsing disease) at baseline (odds ratio 0.37, 95% confidence interval [95% CI] 0.20-0.68) but not with age, sex, or presence of renal or pulmonary disease. Patients were in disease remission during 62% of the study visits. The mean PtGA score during visits immediately prior to relapse was 4.52 points higher (95% CI 0.66-8.4) than that at other remission visits (P = 0.03). PtGA-PhGA discordance is common in GPA. A rise in the PtGA disease activity score during times defined by physicians as periods of remission is associated with subsequent occurrence of disease relapse. These findings support the addition of PtGA as an outcome measure for GPA.
    No preview · Article · Feb 2014 · Arthritis and Rheumatology
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    ABSTRACT: Purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates hepatic LDL receptors, playing a key role in cholesterol metabolism. Gain of function genetic mutations cause autosomal dominant hypercholesterolaemia, while nonsense mutations lower LDL-c and the risk of coronary events. RG7652 (MPSK3169A) is a fully human IgG1 monoclonal antibody (mAb) directed against PCSK9. This first-in-human study evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in healthy individuals with elevated LDL-c. Methods: This Phase I study tested single and multiple doses of RG7652 and placebo given subcutaneously to 80 healthy volunteers with elevated serum LDL-c concentrations. Subjects entered six ascending, single-dose (SD) and four multiple-dose (MD) cohorts allocated 6 active:2 placebo. Two MD cohorts included atorvastatin therapy (40 mg daily) prior to administration of study drug. Following cohort safety reviews, escalation to the next higher dose cohort continued. The primary efficacy endpoint was change in LDL-c 2 weeks after final dose of study drug, with safety follow-up occurring during Weeks 8-16. Results: Eighty subjects (mean age 45 years, range 19-64; 48% male) with mean LDL-c of 162 mg/dL (4.2 mmol/L) were randomised. RG7652 reduced mean LDL-c by as much as 90 mg/dL (60%) from baseline, with a dose-dependent effect that appeared to saturate at the highest doses. The average reduction in LDL-c at Day 15 in SD and Day 36 in MD was >40 mg/dL in all cohorts other than the lowest dose. RG7652 had similar LDL-c lowering effects and kinetics when added to atorvastatin. No dose-limiting safety effects were identified and no subjects discontinued study drug for adverse events (AEs). Thirty-seven AEs, all mild, were attributed to study drug: 27 in 14 RG7652 subjects; 10 in 6 placebo subjects. Conclusions: The anti-PCSK9 mAb, RG7652, safely decreased LDL-c in healthy volunteers with elevated LDL-c as monotherapy and in combination with atorvastatin. The results support further testing of RG7652 in dyslipidaemic patients.
    Full-text · Article · Oct 2013 · Heart (British Cardiac Society)
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    ABSTRACT: Objective: Functional limitations in ankylosing spondylitis (AS) may be due to peripheral joint or axial involvement. To determine if the Bath Ankylosing Spondylitis Functional Index (BASFI), an axial-focused measure, can detect limitations related to peripheral joint involvement equally as well as the Health Assessment Questionnaire modified for the spondyloarthropathies (HAQ-S), a peripheral arthritis-focused measure, and vice versa, we compared associations of each questionnaire with spinal and hip range of motion, peripheral arthritis, and enthesitis in patients with AS. Methods: We examined patients every 4-6 months in this prospective longitudinal study. We used mixed linear models to analyze the associations between 10 physical examination measures and the BASFI and HAQ-S. Results: We studied 411 patients for a median of 1.5 years (median 3 visits). In multivariate analyses, cervical rotation, chest expansion, lateral thoracolumbar flexion, hip motion, tender joint count, and tender enthesis count were equally strongly associated with the BASFI and HAQ-S. Peripheral joint swelling was more strongly associated with the HAQ-S. Individual items of the BASFI were more likely than items of the HAQ-S to be associated with unrelated physical examination measures (e.g., the association between difficulty rising from a chair and cervical rotation), which may have diminished the axial/peripheral distinction for the BASFI. Conclusion: The BASFI and HAQ-S had similar associations with impairments in axial measures, while the HAQ-S had stronger associations with the number of swollen peripheral joints. The HAQ-S should be considered for use in studies focused on spondyloarthritis with peripheral joint involvement.
    No preview · Article · Apr 2013
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    ABSTRACT: Both radiographic damage and functional limitations increase with the duration of ankylosing spondylitis (AS). We examined whether radiographic damage contributed more to functional limitations in late AS than in early AS, and if the strength of association varied with the anatomic region of damage. In this cross-sectional study of 801 patients with AS, we examined associations of the lumbar modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), the cervical mSASSS, lumbar posterior fusion, cervical posterior fusion, and hip arthritis with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire modified for the spondyloarthritides (HAQ-S). Higher lumbar and cervical mSASSS scores were associated with more functional limitations, but there was an interaction between mSASSS scores and the duration of AS, such that the strength of their association with functional limitations decreased with increasing duration of AS. Cervical posterior fusion was associated with worse functioning independent of mSASSS scores. Hip arthritis was significantly associated with functional limitations independent of spinal damage measures. Among patients with AS duration ≥40 years, the number of comorbid conditions accounted for most of the variation in functioning. Results were similar for both the BASFI and the HAQ-S. Although both radiographic damage and functional limitations increase over time in AS, the relative contribution of radiographic damage to functional limitations is lower among patients with longstanding AS than with early AS, suggesting patients may accommodate to limited flexibility. Damage in different skeletal regions impacts functioning over the duration of AS. Functional limitations due to comorbidity supervene in late AS.
    No preview · Article · Feb 2013
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    ABSTRACT: To assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's) (GPA). Subjects were participants in the Wegener's Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 (SF-36) health survey that includes physical and mental component summary scores (PCS and MCS, respectively). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG). The data from 180 subjects in the WGET (median followup 2.3 years, mean number of visits 10) and 237 subjects in the VCRC-LS (median followup 2.0 years, mean number of visits 8) were analyzed. A 1 unit increase in the BVAS/WG corresponded to a 1.15 unit (95% confidence interval [95% CI] 1.02, 1.29) decrease for the PCS and a 0.93 (95% CI 0.78, 1.07) decrease for the MCS in the WGET, and to a 1.16 unit decrease for the PCS (95% CI 0.94, 1.39) and a 0.79 unit decrease for the MCS (95% CI 0.51, 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per 3 months), but worsened slightly (0.03 decrease in PCS every 3 months) among patients not achieving sustained remission (P = 0.005). HRQOL, as measured by the SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA.
    Full-text · Article · Feb 2012
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    ABSTRACT: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients. The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6). We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo. Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.
    Full-text · Article · Jan 2012 · Arthritis research & therapy
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    ABSTRACT: Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).
    Full-text · Article · Dec 2011 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX). Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml. Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC (P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose (P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC. Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.
    Full-text · Article · Dec 2011
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    ABSTRACT: The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA). In the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (i.v.) or 1.0 and 3.5 mg/kg subcutaneously (s.c.), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg s.c., or 5 mg/kg i.v., followed by eight weeks of evaluation. MTRX1011A was well tolerated in the SAD phase up to 7 mg/kg i.v. and in the MD phase up to 1.5 mg/kg s.c.. At weekly doses of 3.5 mg/kg s.c. and 5 mg/kg i.v., a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting. The maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.
    Full-text · Article · Oct 2011 · Arthritis research & therapy
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    ABSTRACT: An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup. The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients.
    Full-text · Article · Aug 2011 · Arthritis & Rheumatology

  • No preview · Conference Paper · May 2011
  • Conference Paper: IgA-ANCA in WG

    No preview · Conference Paper · May 2011
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    ABSTRACT: To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease. We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort. Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11-1.90), diastolic hypertension (OR 1.97, 95% CI 0.98-3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20-0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80). Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.
    Full-text · Article · Apr 2011
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    ABSTRACT: There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener's granulomatosis (WG). Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression. Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47-9.03), P-selectin (OR 6.26, 95% CI 2.78-14.10), PR3-ANCA (OR 9.41, 4.03-21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22-0.57). BVAS/WG increased by 0.80 (95% CI 0.44-1.16), 0.83 (95% CI 0.42-1.25), and 0.81 (95% CI 0.48-1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96-2.12) per unit-increase in MCP-1. Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG.
    No preview · Article · Mar 2011 · The Journal of Rheumatology
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    ABSTRACT: To re-examine the patterns of radiographic involvement in ankylosing spondylitis (AS). This prospective study had institutional review board approval, and 769 patients with AS (556 men, 213 women; mean age, 47.1 years; age range, 18-87 years) provided written informed consent. Radiographs of the cervical spine, lumbar spine, pelvis, and hips were scored by using the Bath Ankylosing Spondylitis Radiology Index (BASRI) by an experienced radiologist. Differences in sacroiliitis grade between right and left sacroiliac joints, frequency of cervical- and lumbar-predominant involvement by sex, frequency of progression to complete spinal fusion, and association between hip arthritis and spinal involvement were computed for the cohort overall and for subgroups defined according to duration of AS in 10-year increments. Symmetric sacroiliitis was seen in 86.1% of patients. Lumbar predominance was more common during the first 20 years of the disease, after which the cervical spine and lumbar spine were equally involved. Men and women were equally likely to have cervical-predominant involvement. Complete spinal fusion was observed in 27.9% of patients with AS for more than 30 years and in 42.6% of patients with AS for more than 40 years. Patients with BASRI hip scores of 2 or greater had significantly higher BASRI spine scores. There were no sex differences in cervical-predominant involvement in AS. Hip arthritis was strongly associated with worse spinal involvement.
    Preview · Article · Oct 2010 · Radiology

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5k Citations
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Institutions

  • 2001-2015
    • University of California, San Francisco
      • Division of Rheumatology
      San Francisco, California, United States
  • 2008
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2007
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, California, United States
  • 2005-2007
    • Boston University
      Boston, Massachusetts, United States
    • University of Alberta
      • Department of Medicine
      Edmonton, Alberta, Canada