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Biomedical subjects

Daniel E Furst

Publications and source records attributed to Daniel E Furst.

At least 37 records · Page 2Linked to original sources
PubMed2005

Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT).

OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Adult↗
PubMed2005

Increased radiographic damage scores at the onset of seropositive rheumatoid arthritis in older patients are associated with osteoarthritis of the hands, but not with more rapid progression of damage.

OBJECTIVE: To investigate the impact of patient age at symptom onset on radiographic joint damage at study entry, and on subsequent progression of damage in a cohort of patients with early seropositive rheumatoid arthritis (RA). METHODS: We studied 186 patients with RA of <15 months' duration. All patients had active disease and had not received disease-modifying antirheumatic drugs. At study entry and during followup, total Sharp scores (TSS), RA-associated joint space narrowing (RA-JSN), and erosions were determined on hand and foot radiographs. Baseline radiographs were also scored for osteoarthritis (OA)-related JSN (OA-JSN) and osteophytes. Older patients (>55 years) and younger patients (</=55 years) were compared by t-test, Mann-Whitney U test, chi-square, or Fisher's exact test. Multiple linear regression models were also constructed. RESULTS: The older group (n = 74) had a higher baseline total Sharp score (median 6.21) compared with the younger group (n = 112) (median 2.33) (P = 0.0002). This was mainly due to a higher baseline JSN score in the older group (median 3.96 versus 1.08) and not to differences in erosion score (median 0.91 versus 0.70). Disease activity and duration of RA symptoms were similar in the 2 groups, as were progression rates of the TSS, JSN score, and erosion score. At baseline, 26% of patients had osteophytes, with a prevalence of 13% in the younger age group and 50% in the older group. The presence of OA-JSN was highly correlated with the presence of osteophytes (r = 0.72). Also, increased age and RA-JSN were associated with increased severity of osteophytes and OA-JSN at baseline. Multiple linear regression analysis showed that both age and hand osteophytes contributed to the increase in baseline RA-JSN score and TSS, but not to erosion score. CONCLUSION: In a cohort of patients with early RA, an increase in the baseline RA-JSN score and TSS can be accounted for in part by the presence of hand OA.

Adult↗
PubMed2005

Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies.

OBJECTIVE: To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. METHODS: Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. RESULTS: At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). CONCLUSION: After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Adult↗
PubMed2005

Systemic sclerosis mortality in the United States: 1979-1998.

The US national mortality rates from systemic sclerosis (SSc) have not been reported since 1979. We studied age, gender and race specific time trends in US national mortality rates of SSc during the period 1979-1998 using poisson regression models. Over the 4.93 billion person-years of observation during the study period, there were 18,126 deaths from SSc, representing a mortality rate of 3.9 per million. The age adjusted mortality rates for men and women were 1.9 and 5.4 per million respectively. There were relatively few deaths in the extremes of age. SSc mortality rates increased with age in both genders and in all racial groups (p<0.001). In multivariable models adjusted for two-way statistical interactions, being African-American, female and of older age were associated with higher death rates. Over the 20 years of observation, overall (age-adjusted) SSc mortality rates showed a 36% increase (p<0.001) and subgroup analyses revealed that the increases were confined to women of both races. This rise occurred during a period in which post-diagnosis survival of SSc is known to have increased, suggesting an increasing incidence of this disease.

Adolescent↗
PubMed2005

Disease-modifying antirheumatic drug use in the elderly rheumatoid arthritis patient.

During the 10-year period since the last review was done by Gardner and Furst, studies have furthered our knowledge of use of disease-modifying antirheumatic drugs (DMARDs) in the elderly rheumatoid arthritis (RA) patient. This article will briefly review the clinical pharmacology of human as they age, and detail the effects of aging on the specific pharmacokinetics and responses to commonly used DMARDs. There has been some progress in understanding the elderly RA patient, however, there is insufficient data for much confidence in DMARDs effects in the elderly.

Aged↗
PubMed2005

COX-2 controversy: where are we and where do we go from here?

Much has been written in the last few months on the association between the cyclooxygenase-2 (COX-2)-selective inhibitors and cardiovascular events. We summarize the randomized controlled studies of different COX-2 inhibitors that led to rofecoxib withdrawal, provide evidence on the differences between various selective coxibs and summarize recommendations from the FDA and the American College of Rheumatology on use of COX-2 inhibitors. We give suggestions on the use of coxibs and briefly mention a general approach to the future of coxibs.

Animals↗
PubMed2005

Meloxicam in rheumatoid arthritis.

Rheumatoid arthritis (RA), a chronic inflammatory multisystem disorder marked by joint pain, stiffness, swelling and multiple systemic involvements, requires a multifaceted approach for its management. It includes symptomatic treatment with analgesics as well as disease-modifying medications to alter the course of RA over time. NSAIDS have been widely used for their symptomatic effects, but their use is not free from adverse effects, which may include life-threatening adverse events such as gastrointestinal (GI) bleeding and perforation. Meloxicam, an oxicam derivative that is a member of the enolic acid group of NSAIDs, has recently been approved by the US FDA for use in RA and osteoarthritis. At the FDA-recommended doses meloxicam is COX-2 preferential. By virtue of this COX-2 preferential activity it is expected to have lower GI toxicity as compared with COX-2 nonselective NSAIDs. Clinical trials have shown that meloxicam at 7.5 - 15 mg/day is as effective as diclofenac, piroxicam and naproxen as an anti-inflammatory and analgesic, and was associated with fewer GI adverse effects.

Animals↗
PubMed2005

Responsiveness of the SF-36 and the Health Assessment Questionnaire Disability Index in a systemic sclerosis clinical trial.

OBJECTIVE: This study compares the responsiveness to change of the Medical Outcomes Study Short Form Health Survey (SF-36), a measure of health related quality of life (HRQOL), and the Health Assessment Questionnaire Disability Index (HAQ-DI), a function instrument, in a randomized clinical trial for treatment of systemic sclerosis (SSc). METHODS: A phase 2/3, multicenter, prospective, placebo controlled trial was conducted to evaluate human recombinant relaxin treatment in patients with diffuse SSc over 24 weeks. At baseline, subjects had stable, moderately severe, diffuse SSc of disease duration < or = 5 years, modified Rodnan skin score > or = 20, serum creatinine < 2.0 mg/dl, percentage forced vital capacity (% FVC) predicted > or = 50%, and % DLCO predicted > or = 40% and were not receiving concomitant disease modifying therapies. Internal consistency reliability of multi-item scales was estimated using Cronbach's alpha. Responsiveness to change of the SF-36 and HAQ-DI was computed between Weeks 0 and 24. Subjects were classified as unchanged or having a meaningful change in 4 different external measures: Change in (1) skin score > or = 30%; (2) % FVC predicted of > or = 15%; (3) self-reported patient global assessment by visual analog scale (VAS) > or = 20%; and (4) physician global assessment by VAS of > or = 20%. Responsiveness indices were computed and Cohen's effect size criteria were used to assess the magnitude of change. RESULTS: A total of 239 patients participated in this trial, with 196 completing the 24 week trial. Cronbach's alpha for the SF-36 scales ranged from 0.76 to 0.93 and for the HAQ-DI ranged from 0.69 to 0.91 (good to excellent). The SF-36 had a larger magnitude of responsiveness in overall disease (patient and physician global assessment) compared to the HAQ-DI, while the HAQ-DI had a larger magnitude of responsiveness in clinical measures (i.e., change in skin score and % FVC predicted) than the SF-36. CONCLUSION: These data support inclusion of both the SF-36 and HAQ-DI as outcome measures in future clinical trials of diffuse SSc.

Adult↗
PubMed2005

Challenges and progress in adverse event ascertainment and reporting in clinical trials.

Toxicity, safety, and tolerability are integral facets of patient risk/benefit decisions, yet the capacity to define, measure, and compare these aspects is underdeveloped compared to aspects of efficacy. There are many reasons for this, scientific and administrative, but all are surmountable. Probably the greatest primary obstacle is the absence of a measurement instrument designed specifically for this purpose. There are increasing calls from various stakeholders for better evidence, and therefore better ascertainment, in this area, especially in randomized trials, and for these reasons OMERACT began deliberations about these concepts in 1994. A prototype coding instrument (the Rheumatology Common Toxicity Criteria) was developed and discussed at OMERACT 5. In the 2 years before OMERACT 7, a process of concept development and iterative design and testing were conducted to develop a patient self-report and investigator-reported adverse event instruments designed for use in trials at the time of visit. The predominant workload is performed by the patient in a self-report checklist, which is then mapped by the trialist onto a medically sophisticated version. This article presents background on the process of developing a dual adverse event instrument, which was presented and critically discussed in detail at OMERACT 7.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Standardized assessment of adverse events in rheumatology clinical trials: summary of the OMERACT 7 drug safety module update.

A presentation, demonstration, and discussion of recently developed adverse event instruments were the topics for the OMERACT 7 Drug Safety Module. The module began with a plenary introducing the needs and challenges of adverse event ascertainment. It was followed by a review of module work from previous OMERACT meetings on a prototype coding instrument (Rheumatology Common Toxicity Criteria), then a brief description of the process behind the recently developed patient self-report and investigator report adverse event instruments. These current instruments are designed for use in controlled trials although they could be used in other settings. The instruments rely primarily on patient self-reporting using a checklist, which the investigator then folds into a parallel structured but more medically sophisticated instrument. In pilot testing, this innovative dual-use system has shown reliability and acceptability, while preserving validity. A "stakeholder panel" of representatives from 8 sectors followed--patient, nurse investigator, regulator, clinician scientist, industry, OMERACT, global public health/WHO, and Cochrane Collaboration--for their perspectives on the needs, challenges, and potential ways forward for adverse event ascertainment and reporting in clinical trials. At the breakout session small focus groups participated in hands-on interactive testing of one of 3 versions of the instruments, which differ in degree of comprehensiveness. Each focus group had a participatory patient with rheumatoid arthritis. At a second plenary there was group feedback by rapporteurs and presentation of results from pilot studies of iterative testing of validity, reliability, and feasibility of the instruments. During plenary discussion a frequent suggestion for improvement was to refine the process so that event ascertainment could be done entirely using the patient instrument with minimal input from the investigator at the visit, if patient-investigator agreement was high. Most found the patient checklist attractive, particularly if the patient instrument was shown to be reliable and valid. Finally, a future research agenda was discussed.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

A phase 2 dose-finding study of PEGylated recombinant methionyl human soluble tumor necrosis factor type I in patients with rheumatoid arthritis.

OBJECTIVE: In a phase 2 study, to assess the efficacy and safety of pegsunercept, a soluble tumor necrosis factor receptor type I, for the treatment of rheumatoid arthritis (RA). METHODS: Patients were randomized to receive weekly subcutaneous injections of placebo (n = 61) or active drug [400 microg/kg (n = 67) or 800 microg/kg (n = 66)] for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. Secondary efficacy measures included ACR50 and ACR70 responses, and changes in individual ACR components at Week 12. Safety assessments included summaries of adverse events including infectious episodes. RESULTS: Treatment with pegsunercept resulted in a significantly higher ACR20 response at Week 12 in the 800 microg/kg group (45%) compared with the placebo group (26%; p = 0.020). The treatment effect of pegsunercept (both doses) over the study period showed statistically significant improvement for most ACR components and health related quality of life, with the 800 microg/kg group showing greater clinical improvements in efficacy measures. The overall incidence of adverse events and infectious episodes was similar among the treatment and placebo groups. CONCLUSION: In this 12 week dose-finding study of 194 patients, weekly subcutaneous dosing with pegsunercept showed beneficial effects in improving the signs and symptoms of RA. It appeared to be safe and well tolerated in this small number of patients. Significant clinical improvements were seen in patients in the 800 microg/kg group; however, this dose may be suboptimal, and further evaluation of this product with higher doses or a more frequent dosing regimen is warranted.

Adult↗
PubMed2005

Outcome measures for acute and chronic gout.

Gout provides some unique challenges in classification and measurement of outcomes. Our aim was to evaluate criteria for classification and to develop and validate optimal instruments to measure outcomes for acute and chronic gout. A planning committee and interested attendees met to propose classification criteria and domains for outcomes. Seven of the current American Rheumatism Association preliminary criteria for classification were proposed as the best current criteria for acute gouty arthritis, pending further studies. The presence of gout is best established by crystal identification, although this technique has limitations. Five domains for acute gout outcomes and 9 for chronic gout were identified along with proposed instruments for testing and validation. The unique problems of gout evaluation can and will be addressed.

Acute Disease↗
PubMed2005

Scleroderma--developing measures of response.

The scleroderma research community continued its focus on the development and proper validation of the outcome measures for clinical trials in scleroderma during the special interest group meeting at OMERACT 7. Deliberations focused on progress in the assessment of gastrointestinal disease, renal physiology, vascular damage, and the unique challenges inherent in studying pediatric patients with scleroderma.

Adolescent↗
PubMed2004

Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: studies of healthy women and women with scleroderma.

OBJECTIVE: Microchimerism (Mc), originating from bidirectional fetal-maternal cell traffic during pregnancy, has recently been identified in healthy adults and in patients with scleroderma (systemic sclerosis [SSc]). This study was undertaken to investigate the frequency and quantitative levels of maternal Mc (MMc) in healthy women and women with SSc. METHODS: HLA-specific primers and fluorogenic probes were used in real-time quantitative polymerase chain reaction assays to detect and quantify MMc by targeting noninherited, nonshared HLA sequences. DNA-based HLA typing was conducted in 67 proband-mother pairs and in all children if the proband was parous. Statistical analysis was limited to 50 proband-mother pairs (including 32 healthy women and 18 women with SSc) in whom MMc could be distinguished from potential fetal Mc. RESULTS: MMc in peripheral blood mononuclear cells was more frequent among women with SSc (72%) than healthy women (22%) (odds ratio 9.3, P = 0.001). However, levels of MMc, expressed as the genome equivalent of maternal cells per million (gEq/mil), were not significantly different (0-68.6 gEq/mil in SSc patients, 0-54.5 in healthy women). In additional studies, positivity for MMc was demonstrated in a bone marrow aspirate from an SSc patient in whom peripheral blood had been found to be negative for MMc on 4 occasions, and tissue from a subsequent autopsy of this patient had MMc levels of 757 and 1,489 gEq/mil in the lung and heart, respectively. CONCLUSION: MMc is not uncommon in the peripheral blood of healthy adults, is increased in frequency in patients with SSc, and may be present in bone marrow and disease-affected tissues although absent in the peripheral blood.

Adolescent↗
PubMed2004

Regional differences in bronchoalveolar lavage and thoracic high-resolution computed tomography results in dyspneic patients with systemic sclerosis.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). Although early identification and treatment of alveolitis may prevent deterioration of lung function, the best approach for diagnosing active alveolitis remains controversial. This study was undertaken to investigate the utility of high-resolution computed tomography (HRCT) of the chest, in comparison with bronchoalveolar lavage (BAL), in the diagnosis of alveolitis in these patients. METHODS: Eighteen patients with SSc and dyspnea were evaluated for ILD by pulmonary function testing and bronchoalveolar lavage (BAL), and 15 of these patients underwent chest HRCT. BAL was performed in either the middle lobe or the lingula, and also in a lower lung segment. Differential cell counts were determined by clinical cytopathology, with retrospective recounting in a blinded manner by a single technician. Active alveolitis was defined as the presence of > or =3.0% polymorphonuclear cells and/or > or =2% eosinophils in BAL fluid. BAL fluids were cultured for bacteria, mycobacteria, and fungi. HRCT scans were evaluated in a blinded manner for ground-glass opacification and fibrosis in the lavaged lobes. RESULTS: Nine of the 18 patients had active alveolitis recorded in both lavaged segments, while in 4 patients it was recorded in only 1 segment (lower lobe in 3). Following repeat differential cell counting, 3 patients were reclassified as having active alveolitis and 1 as having no alveolitis. Culture of BAL fluid identified clinically unsuspected infection in 3 patients. For the right middle lung lobe or lingula there was excellent agreement between ground-glass opacification and the finding of alveolitis on BAL from segments in the same lung regions, but this was not observed for the lower lobes. The correlation between fibrosis on HRCT and the presence of alveolitis on BAL was significant for the lower lobes but not the middle lung fields. CONCLUSION: BAL of the middle lobe or lingula may underestimate the presence of active alveolitis. Similarly, while ground-glass opacification on HRCT accurately predicted alveolitis in the middle lung fields, HRCT did not detect all sites of inflammation and did not identify infectious etiologies. These data suggest that, in addition to HRCT, BAL with lavage, differential cell counting, and culture from at least 2 segments of lung be performed for diagnosing SSc alveolitis.

Adult↗
PubMed2004

Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases).

To ascertain the consequences of severe leukopenia and the tempo of recovery, we studied the immunity of 56 adult patients treated for multiple sclerosis or systemic sclerosis with autologous CD34 cell transplantation using extremely lymphoablative conditioning. NK cell, monocyte, and neutrophil counts recovered to normal by 1 month; dendritic cell and B cell counts by 6 months; and T cell counts by 2 years posttransplant, although CD4 T cell counts remained borderline low. Initial peripheral expansion was robust for CD8 T cells but only moderate for CD4 T cells. Subsequent thymopoiesis was slow, especially in older patients. Importantly, levels of antibodies, including autoantibodies, did not drop substantially. Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7-24 months posttransplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pretransplant plasma cells.

Adult↗
PubMed2004

Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis.

BACKGROUND: Interleukin-1 (IL-1) plays an important role in the pathophysiology and progression of rheumatoid arthritis (RA) by contributing to destruction of cartilage, bone, and periarticular tissues. Inhibiting IL-1 synthesis or activity with the use of recombinant human IL-1 receptor antagonist (anakinra) may prove to be an effective approach to the treatment of RA. OBJECTIVE: The purpose of this article is to review the effects of anakinra in the treatment of RA. METHODS: A MEDLINE search from 1982 to 2003 was used to identify animal studies and randomized clinical trials of anakinra and other therapies that target IL-1. RESULTS: Clinical trials of anakinra have shown that it reduces the signs and symptoms of active disease and slows the rate of radiographic destruction in adults with RA. With anakinra 150 mg/d, 43% of patients achieved an American College of Rheumatology (ACR) 20% response, compared with 27% with placebo (P = 0.014). The ACR20 score indicates at least 20% improvement in the ACR composite score, which includes assessment of tender and swollen joint count, and other clinical end points such as pain and disability assessment. Patients treated with anakinra also experienced a 59% reduction in new bony erosion compared with controls (P < 0.001) and a 65% reduction in joint space narrowing as measured by the modified Sharp score (P = 0.020). Injection-site reactions were the most commonly reported adverse event, occurring in 50%, 73%, and 81% of patients receiving anakinra 30, 75, and 150 mg/d, respectively, compared with 25% of patients receiving placebo. Few serious adverse events were reported, and they typically occurred in patients receiving the highest daily dosage. CONCLUSIONS: IL-1 is an important cytokine in promoting the damage associated with RA. Anakinra is mildly to moderately effective and well tolerated in patients with active RA when used as monotherapy or in combination with methotrexate.

Adult↗