Grace S. Park

Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial.

BACKGROUND Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF. OBJECTIVE To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF. DESIGN Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907). SETTING 6 U.S. sites. PATIENTS Patients with FMF aged 4 years or older with 1 or more attacks per month. INTERVENTION One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo. MEASUREMENTS Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo. RESULTS 8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95% CI, -3.4 to -0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events. LIMITATION Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations. CONCLUSION Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. PRIMARY FUNDING SOURCE U.S. Food and Drug Administration, Office of Orphan Products Development.

Minimally important difference in diffuse systemic sclerosis: results from the d-penicillamine study

Objective: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire—Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). Participants and methods: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose d-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient’s health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. Results: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40–0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15–0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9–14.2 (0.86–1.77 effect size) on the mRSS and 0.21–0.55 (0.32–0.83 effect size) on the HAQ-DI score. Conclusion: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.

Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis.

OBJECTIVE To characterize the antiinflammatory function of high-density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL-associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL. METHODS We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell-free assay, and proinflammatory HDL was defined by an HDL inflammatory index > or =1. Plasma and HDL-associated protein levels of apolipoprotein A-I (Apo A-I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme-linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay. RESULTS Age, disease activity, the presence of erosive disease, non-Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A-I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001). CONCLUSION Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality.

Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment

Objectives To compare health-related quality of life (HRQoL) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis using spydergram representations. Methods Data from randomised, controlled trials of etanercept in patients with RA, PsA and psoriasis were analysed. HRQoL was assessed by the medical outcomes survey short form 36 (SF-36) physical (PCS) and mental (MCS) component summary and domain scores. Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure. Results Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA, but near normative values in patients with psoriasis; MCS scores at baseline were near normal in PsA and psoriasis but low in RA. Treatment with etanercept resulted in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications. Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA; clinically meaningful improvements in SF-6D were observed in all three patient populations following treatment with etanercept. Conclusions Patients with RA, PsA and psoriasis demonstrated unique HRQoL profiles at baseline. Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA, PsA and psoriasis.

Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis

To evaluate the long‐term safety and efficacy of etanercept therapy in rheumatoid arthritis (RA) patients.

A pilot study of subclinical coronary atherosclerosis in systemic sclerosis: coronary artery calcification in cases and controls.

OBJECTIVE Systemic sclerosis (SSc) is associated with vasculopathy and endothelial cell injury, which could potentially increase the risk of coronary atherosclerosis. Multidetector computed tomography, a noninvasive procedure, generates a coronary calcium score (CCS) as a marker for coronary atherosclerosis. Serum proinflammatory high-density lipoprotein (piHDL) is a potential novel marker of atherosclerotic risk. The objective of the pilot study was to determine 1) the prevalence of subclinical coronary atherosclerosis in SSc and 2) serum piHDL levels as a potential novel marker of atherosclerotic risk in SSc. METHODS A cross-sectional study of 17 patients with SSc and 17 age-, sex-, and race-matched healthy controls in Cincinnati, Ohio, was conducted. Measurements included CCS; body mass index; lipid profile; and serum levels of high-sensitivity C-reactive protein, homocysteine, and piHDL. RESULTS Patients with SSc were slightly older (mean 52.8 years) than control subjects (mean 50.6 years; P = 0.01). Coronary calcium was found in 12 participants (9 with SSc, 3 controls; P = 0.03). The mean +/- SD CCS in patients with SSc was significantly greater than the controls (126.6 +/- 251.0 versus 14.7 +/- 52.2; P = 0.003). Five patients with SSc (29%), but no controls, had detectable levels of piHDL (P = 0.06). CONCLUSION Prevalence of subclinical coronary atherosclerosis is greater in patients with SSc compared with healthy controls. These findings should be confirmed in a larger study.

Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis

To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls (p< or =0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups (p< or =0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDLs anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality.

Early Trends From the Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS)

BACKGROUND Launched in January 2011, the prospective payment system (PPS) for the US Medicare End-Stage Renal Disease Program bundled payment for services previously reimbursed independently. Small dialysis organizations may be particularly susceptible to the financial implications of the PPS. The ongoing Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS) was designed to describe trends in care and outcomes over the period of PPS implementation. This report details early results between October 2010 and June 2011. STUDY DESIGN Prospective observational cohort study of patients from a sample of 51 small dialysis organizations. SETTING & PARTICIPANTS 1,873 adult hemodialysis and peritoneal dialysis patients. OUTCOMES Secular trends in processes of care, anemia, metabolic bone disease management, and red blood cell transfusions. MEASUREMENTS Facility-level data are collected quarterly. Patient characteristics were collected at enrollment and scheduled intervals thereafter. Clinical outcomes are collected on an ongoing basis. RESULTS Over time, no significant changes were observed in patient to staff ratios. There was a temporal trend toward greater use of peritoneal dialysis (from 2.4% to 3.6%; P = 0.09). Use of cinacalcet, phosphate binders, and oral vitamin D increased; intravenous (IV) vitamin D use decreased (P for trend for all <0.001). Parathyroid hormone levels increased (from 273 to 324 pg/dL; P < 0.001). Erythropoiesis-stimulating agent doses decreased (P < 0.001 for IV epoetin alfa and IV darbepoetin alfa), particularly high doses. Mean hemoglobin levels decreased (P < 0.001), the percentage of patients with hemoglobin levels <10 g/dL increased (from 12.7% to 16.8%), and transfusion rates increased (from 14.3 to 19.6/100 person-years; P = 0.1). Changes in anemia management were more pronounced for African American patients. LIMITATIONS Limited data were available for the prebundle period. Secular trends may be subject to the ecologic fallacy and are not causal in nature. CONCLUSIONS In the period after PPS implementation, IV vitamin D use decreased, use of oral therapies for metabolic bone disease increased, erythropoiesis-stimulating agent use and hemoglobin levels decreased, and transfusion rates increased numerically.

Predicting low disease activity and remission using early treatment response to antitumour necrosis factor therapy in patients with rheumatoid arthritis: exploratory analyses from the TEMPO trial

Objective To derive and validate decision trees to categorise rheumatoid arthritis (RA) patients 12 weeks after starting etanercept with or without methotrexate into three groups: patients predicted to achieve low disease activity (LDA) at 1 year; patients predicted not to achieve LDA at 1 year and patients who needed additional time on therapy to be categorised. Methods Data from RA patients enrolled in the TEMPO trial were analysed. Classification and regression trees were used to develop and validate decision tree models with week 12 and earlier assessments that predicted long-term LDA. LDA, defined as disease activity score in 28 joints (DAS28) ≤3.2 or clinical disease activity index ≤10.0, was measured at 52 or 48 weeks. Demographics, laboratory data and clinical data at baseline and to week 12 were analysed as predictors of response. Results 39% (67/172) of patients receiving etanercept and 60% (115/193) of patients receiving etanercept plus methotrexate achieved LDA at week 52. For patients receiving etanercept, 53% were predicted to have LDA, 39% were predicted not to have LDA and 8% could not be categorised using DAS28 criteria at week 12. For patients receiving etanercept plus methotrexate, 63% were predicted to have LDA, 25% were predicted not to have LDA and 12% could not be categorised. Conclusion Most (80–90%) patients in TEMPO initiating etanercept with or without methotrexate could be predicted within 12 weeks of starting therapy as likely to have LDA or not at week 52. However, approximately 10–20% of patients needed additional time on therapy to decide whether to continue treatment.

Disease Progression and Treatment Responses in a Prospective DMARD-naïve Seropositive Early Rheumatoid Arthritis Cohort: Does Gender Matter?

Objective. To assess gender differences in disease characteristics and treatment responses over time in a disease-modifying antirheumatic drug (DMARD)-naive seropositive early rheumatoid arthritis (RA) cohort. Methods. Patients with polyarticular disease who were DMARD-naive and had seropositive early RA (< 14 months) were recruited by the Western Consortium of Practicing Rheumatologists. Each patient was examined at study entry, after 6 and 12 months, and yearly thereafter. Clinical and demographic data were collected. We investigated gender differences in baseline disease characteristics and treatment using chi-squared, Mann-Whitney U, and t tests. We used generalized estimating equations (GEE) models for repeated measures to examine whether the rate of change of specific disease outcomes during the first 2 years after DMARD initiation was significantly influenced by gender. Results. At baseline, men (n = 67) and women (n = 225) had similar disease activity and radiographic damage; men, however, had significantly worse erosion, while women had worse joint space narrowing. Despite similar treatment, women had worse disease progression over the 2-year followup, as assessed by trends in Disease Activity Score 28/erythrocyte sedimentation rate (DAS28-ESR4), physician global scores, and tender joint counts. In the GEE model, gender was significantly associated with the rate of change of DAS28-ESR4 scores (p = 0.009), although not independently associated with disease activity. Self-reported measures (Health Assessment Questionnaire-Disability Index, patient global scores, fatigue, pain) were worse among women at baseline and throughout the study period. Men were more likely to achieve remission. Conclusion. At baseline, men and women had similar disease activity and joint damage. Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment.