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1.  Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study 
Systemic sclerosis (SSc) is a clinically heterogeneous, life-threatening disease characterized by fibrosis, microvasculopathy, and autoimmunity. Extensive nonclinical and clinical data implicate B cells in the pathogenesis of SSc. MEDI-551 is an investigational humanized monoclonal antibody that targets the B cell surface antigen CD19 and mediates antibody-dependent, cell-mediated cytotoxicity of B cells. This clinical study evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of MEDI-551 in subjects with SSc.
This phase I multicenter, randomized, double-blind, placebo-controlled, single escalating dose study enrolled adult subjects with either limited or diffuse cutaneous SSc. A single intravenous dose of MEDI-551 was administered, and safety and tolerability were evaluated. MEDI-551 pharmacokinetics (PK), pharmacodynamics, and immunogenicity were also assessed. Safety assessments included the incidence of adverse events and changes in clinical and laboratory results. MEDI-551 serum concentrations, effects on circulating and tissue B cells and plasma cells (PCs), and antidrug antibodies were analyzed. Modified Rodnan skin score (MRSS) and pulmonary function tests were used to explore the clinical effect of MEDI-551.
The study enrolled 28 subjects with SSc (mean age, 47.3 years; 67.9 % female). Twenty-four received a single dose of MEDI-551 (0.1–10.0 mg/kg) and four received placebo. Treatment-emergent adverse events (TEAEs) occurred in 95.8 % of subjects in the MEDI-551 group and in 75.0 % of subjects in the placebo group; the majority of TEAEs were mild or moderate in severity. Two serious adverse events were considered possibly related to the study drug. One death, deemed not related to the study drug, occurred in a MEDI-551-treated subject. MEDI-551 exhibited linear PK in the dose range of 1.0 to 10.0 mg/kg, and more rapid clearance at lower doses. Dose-dependent depletion of circulating B cells and plasma cells was observed. MRSS assessments suggest a possible clinical effect of MEDI-551 on affected skin.
A single escalating dose of MEDI-551 was tolerable and safe in this subject population. B cell depletion was achieved and was dose dependent. A signal of clinical effect was observed. Based on these results, further investigation of MEDI-551 as a disease-modifying treatment for SSc is warranted.
Trial registration identifier, NCT00946699; registered 23 July 2009.
PMCID: PMC4895815  PMID: 27267753
B cells; CD19; Pharmacokinetics; Pharmacodynamics; Scleroderma; Systemic sclerosis
2.  Isolated radial scar diagnosis by core-needle biopsy: Is surgical excision necessary? 
SpringerPlus  2016;5:398.
Radial scar and radial sclerosis (RS) are considered benign breast lesions with proliferative features. There is sparse literature on frequency of cancer upgrade in these patients without atypical features found on image-guided needle biopsy. This study retrospectively reviews cases of isolated RS diagnosed on needle biopsy and evaluates the cancer upgrade after subsequent surgical excision.
We conducted a retrospective cross-sectional study of cases with an isolated RS diagnosis based on needle biopsy and subsequent surgical pathology among all patients between January 1, 2009 and December 31, 2013. Patients with concomitant atypia, lobular carcinoma in situ on core biopsy, complete excision of very small RS with needle biopsy, and radiology-pathology discordance were excluded. An upgrade from the needle biopsy of RS was defined as surgical excision pathology that revealed ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), and/or invasive lobular carcinoma (ILC).
10,921 image-guided needle biopsy pathology reports were collected and 88 patients (0.81 %) were identified as having isolated RS. Of these 88 patients, 63 (72 %) underwent excision. The upgrade rate to cancer on subsequent surgical excision was 1.59 % (1/63) for DCIS; 0 % (0/63) for IDC; and 0 % (0/63) ILC. Twenty-five patients who did not undergo surgical excision had stable imaging studies with mean (±SD) 26 (±20) months follow up.
Isolated radial scar on needle biopsy may not warrant routine surgical excision given relatively low cancer upgrade rates. Advancement in breast imaging, pathology and multidisciplinary approaches to care may effectively guide non-surgical management of RS.
PMCID: PMC4816959  PMID: 27047724
Breast cancer; Radial scar; Radial sclerosis; Surgical management; Benign breast disease
3.  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Oral Type I Collagen Treatment in Patients With Diffuse Cutaneous Systemic Sclerosis 
Arthritis and rheumatism  2008;58(6):1810-1822.
To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dc-SSc; scleroderma) for ≤10 years.
One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 µg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed.
Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 –7.9 versus −2.9; P = 0.0063).
Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.
PMCID: PMC4511098  PMID: 18512816
4.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient reported outcomes and the ability of candidate measures to predict later good x-ray and functional outcomes.
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2 year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
We propose two new definitions of remission both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected in each trial as an outcome and that the results on both be reported in each trial.
PMCID: PMC3115717  PMID: 21294106
5.  Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma 
Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics.
Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both.
In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation.
In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.
Trial registration
ClinicalTrials (NCT): NCT00507130 and ClinicalTrials (NCT): NCT00590720
PMCID: PMC3058114  PMID: 21356110
6.  Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus 
Arthritis Research & Therapy  2010;12(Suppl 1):S6.
Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy.
PMCID: PMC2991779  PMID: 20392292
7.  Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus 
To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.
PMCID: PMC2950308  PMID: 20948567
8.  Correction: Type I Interferon: Potential Therapeutic Target for Psoriasis? 
PLoS ONE  2009;4(3):10.1371/annotation/fbcbcab9-2e87-4ec7-af6e-c6e9e64ad4b3.
PMCID: PMC2665006
9.  Effects of 1-Year Treatment with Cyclophosphamide on Outcomes at 2 Years in Scleroderma Lung Disease 
Rationale: The Scleroderma Lung Study enrolled 158 patients with scleroderma-related interstitial lung disease in a placebo-controlled trial of oral cyclophosphamide (CYC). Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of benefit beyond 1 year was unclear.
Objectives: A second year of follow-up was performed to determine if these effects persisted after stopping treatment.
Methods: A detailed analysis of data obtained over the two years of the study was performed.
Measurements and Main Results: Using a longitudinal joint model, we analyzed FVC, total lung capacity, transitional dyspnea index, Rodnan skin scores, and the Health Assessment Questionnaire–Disability Index during the second year, after adjusting for baseline values, baseline fibrosis score, and nonignorable missing data. Evaluable subjects (72 CYC; 73 placebo) included 93 who completed all visits plus 52 who completed at least 6 months of therapy and returned at 24 month or had their 24-month data imputed. The beneficial effects of CYC on pulmonary function and health status continued to increase through 18 months, after which they dissipated, whereas skin improvements dissipated after 12 months. In contrast, the positive effect on dyspnea persisted through 24 months. Adverse events were uncommon.
Conclusions: One year of CYC improved lung function, skin scores, dyspnea, and health status/disability, effects which either persisted or increased further for several months after stopping therapy. However, except for a sustained impact on dyspnea, all of these effects waned and were no longer apparent at 24 months. Treatment strategies aimed at extending the positive therapeutic effects observed with CYC should be considered.
Clinical trial registered with (NCT 000004563).
PMCID: PMC2078679  PMID: 17717203
cyclophosphamide; interstitial lung disease; scleroderma; systemic sclerosis
10.  Type I Interferon: Potential Therapeutic Target for Psoriasis? 
PLoS ONE  2008;3(7):e2737.
Psoriasis is an immune-mediated disease characterized by aberrant epidermal differentiation, surface scale formation, and marked cutaneous inflammation. To better understand the pathogenesis of this disease and identify potential mediators, we used whole genome array analysis to profile paired lesional and nonlesional psoriatic skin and skin from healthy donors.
Methodology/Principal Findings
We observed robust overexpression of type I interferon (IFN)–inducible genes and genomic signatures that indicate T cell and dendritic cell infiltration in lesional skin. Up-regulation of mRNAs for IFN-α subtypes was observed in lesional skin compared with nonlesional skin. Enrichment of mature dendritic cells and 2 type I IFN–inducible proteins, STAT1 and ISG15, were observed in the majority of lesional skin biopsies. Concordant overexpression of IFN-γ and TNF-α–inducible gene signatures occurred at the same disease sites.
Up-regulation of TNF-α and elevation of the TNF-α–inducible gene signature in lesional skin underscore the importance of this cytokine in psoriasis; these data describe a molecular basis for the therapeutic activity of anti–TNF-α agents. Furthermore, these findings implicate type I IFNs in the pathogenesis of psoriasis. Consistent and significant up-regulation of type I IFNs and their associated gene signatures in psoriatic skin suggest that type I IFNs may be potential therapeutic targets in psoriasis treatment.
PMCID: PMC2481274  PMID: 18648529
11.  Assessing Body Image in Patients with Systemic Sclerosis (Scleroderma): Validation of the Adapted Satisfaction With Appearance Scale 
Body image  2007;4(1):79-86.
People with scleroderma often experience disfiguring appearance-related changes in socially visible and interpersonally salient areas. Although disfigurement can lead to body image dissatisfaction, this phenomenon has not been well investigated due to the lack of a disfigurement-specific measure. The Satisfaction With Appearance (SWAP) scale, previously developed in burn survivors, was adapted and administered to 254 participants with scleroderma to evaluate its psychometric integrity and its validity for use in a different medical population that experiences changes in appearance. Principal component analysis revealed two factors – Subjective Dissatisfaction and Perceived Social Impact—rather than the four found in burn victims. Excellent estimates of internal consistency and temporal stability and strong evidence for the reliability of the two-factor solution were found. The resulting factor structure in a scleroderma populations suggest that differing medical conditions may create alternate constellations of BID, reflects the need for body image researchers to assess psychometrics across medical populations and may have clinical implications for BID interventions.
PMCID: PMC2031840  PMID: 18089254
Body image; Scleroderma; Disfigurement; Social impact; Assessment
12.  Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: Case study and review of the literature 
Neuro-Oncology  2004;6(3):259-263.
Donor-acquired solid organ malignancy is a rare complication of organ transplantation. We report a case of a patient who received bilateral lung transplants for pulmonary fibrosis from a donor with known glioblastoma multiforme (GBM). The lungs, heart, liver, and kidneys were harvested after a lethal intracranial bleed and accepted for transplantation by four centers. An enlarged hilar lymph node sampled at the time of transplant was found to contain GBM. Four months later, the patient developed diffuse interstitial pulmonary infiltrates with mediastinal lymphadenopathy. Lung biopsy confirmed metastatic GBM. The patient died 2 weeks after the diagnosis was established. The patient receiving the donor liver also developed GBM. We present a case study, review of the literature, and suggested interventions to minimize the risk of transmission.
PMCID: PMC1871995  PMID: 15279719
15.  Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study 
Annals of the Rheumatic Diseases  2011;70(9):1542-1549.
To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA).
A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. Subjects received single intravenous escalating doses of mavrilimumab (0.01–10.0 mg/kg) or placebo.
32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks.
In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA.
Trial registration number: NCT00771420.
PMCID: PMC3147227  PMID: 21613310
16.  Acute Perforated Peptic Ulcer 
British Medical Journal  1950;1(4647):211-215.
PMCID: PMC2036627  PMID: 15404993

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