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Biomedical subjects

K L Sewell

Publications and source records attributed to K L Sewell.

At least 19 recordsLinked to original sources
PubMed2005

Gene polymorphisms and serological markers of patients with active Crohn's disease in a clinical trial of antisense to ICAM-1.

Serological profiles for anti-Saccharomyces cerevisiae antibodies (ASCA)/ perinuclear antineutrophil cytoplasmic antibodies (pANCA) and gene polymorphisms in tumour necrosis factor (TNF)-alpha and intercellular adhesion molecule-1 (ICAM-1) are associated with occurrence and/or outcome in Crohn's disease. The aim of the study was to characterize the ASCA/pANCA profile, soluble ICAM-1 expression and single nucleotide gene polymorphisms (SNPs) in TNF-alpha and ICAM-1 genes. Crohn's patients with moderate disease activity were enrolled in a clinical trial of Alicaforsen (ISIS 2302). Peripheral blood samples were collected prospectively for serum studies and for potential analysis of gene polymorphisms. A multivariate analysis was performed to compare treatment effect with the biomarkers studied. Serological testing for ASCA/pANCA was obtained for 257 patients at baseline: 37% were ASCA(+)/pANCA(-) (Crohn's pattern), 9% had both markers, 15% were ASCA(-)/pANCA(+) and 39% had neither marker. When the data were analysed by multiple regression analysis, a trend was found within the Alicaforsen-treated groups for greater rates of remission in the ASCA(+)/pANCA(-) subgroup versus all other serological profiles (25 versus 14%, P = 0.068), but not versus the placebo remission rate (18.8%). Gene polymorphisms were assessed in 64 patients, 21 from the placebo group. ICAM-1 assessment revealed no over-representation. However, three unique TNF-alpha SNPs were identified that correlated significantly with remission; sites 290 (P = 0.0253), -2735 (P = 0.0317) and -3090 (P = 0.0067). Although the overall clinical trial was negative, we have identified a trend towards clinical remission with Alicaforsen therapy in a subgroup of patients with Crohn's disease expressing ASCA(+)/pANCA(-). Furthermore, we have identified three TNF-alpha SNPs that may also predict a positive therapeutic outcome.

Adolescent↗
PubMed2002

Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn's disease.

BACKGROUND AND AIMS: To evaluate the safety, pharmacokinetics and clinical efficacy of the intercellular adhesion molecule-1 antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) at 250-350 mg in Crohn's disease. METHODS: : Patients (> 50 kg) with active Crohn's disease (Crohn's disease activity index > or = 220) were assigned by gender, randomly, to two alicaforsen treatment groups: 300 or 350 mg, infused intravenously three times a week for 4 weeks. All patients weighing 36-50 kg received 250 mg of alicaforsen. Background aminosalicylates, antibiotics, immunosuppressives and corticosteroids were permitted, but tumour necrosis factor-alphainhibitors were prohibited. The primary end-point was clinical remission (Crohn's disease activity index < or = 150). RESULTS: Twenty-two patients were enrolled with a mean baseline Crohn's disease activity index of 304. Steroids were used by 27%, 5-aminosalicylic acid by 68% and immunosuppressives by 27%; 23% had previously received infliximab. Five subjects withdrew after one to three infusions for infusion-related symptoms. Nine patients (41%) experienced clinical remission. Fifty-three per cent of the evaluable subjects receiving more than three infusions experienced remission (18% at week 8; 29% at week 12). The overall response, using a minimum decrease of 70 in the Crohn's disease activity index, was 41-47% for the evaluable group, at weeks 8 and 12. The median duration of remission was 14 weeks. Plasma pharmacokinetic results showed overlapping levels (Cmax, AUC) for the three doses. The infusion-related reaction profile consisted of fever, chills, headache, nausea, emesis or arthralgias, typically occurring 2-4 h after completion of the first infusion. Reactions were less frequent in patients receiving background corticosteroids. The 2-4-h transient post-infusion partial thromboplastin time prolongation values, a class effect of phosphorothioate oligonucleotides, were 18, 21 and 23 s for 250, 300 and 350 mg, respectively. CONCLUSIONS: Alicaforsen (ISIS 2302), at fixed doses of 300 and 350 mg, achieved the desired drug exposure and may be an effective therapy for Crohn's disease. Infusion-related reactions were observed less frequently in patients on corticosteroids, and with decreasing frequency with continued treatment.

Adolescent↗
PubMed1999

Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.

Adolescent↗
PubMed1998

Rheumatoid arthritis in older adults.

Rheumatoid arthritis is a common problem in older adults with varied clinical presentations, which can present a diagnostic challenge. Patients experience a significant functional decline and are placed at increased risk of institutionalization. Multidisciplinary care should focus on all factors contributing to disability, including pain management and depression. Current therapeutic modalities offer an array of choices to the geriatrician. Drug selection should be individualized to reflect each patient's level of disease activity and risk for specific toxicities.

Aged↗
PubMed1997

Calcitonin.

Explore the source record for details and available documents.

Administration, Inhalation↗
PubMed1997

Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene.

OBJECTIVE: To evaluate the efficacy of systemic and intraarticular adenoviral transfer of a modified tumor necrosis factor alpha receptor (TNF alphaR) gene and its expression in rat collagen-induced arthritis (CIA). METHODS: Rats with CIA received injections of replication-deficient adenovirus containing either a TNF alpha inhibitor (TNFI) gene or a control beta-galactosidase (beta-gal) gene. The TNFI gene codes for a fusion protein consisting of the human 55-kd TNF alphaR and a mouse IgG heavy chain. Successful gene transfer was determined by serum TNF alphaR measurements and by histologic examination of injected joints with in situ blue staining. RESULTS: Serum TNF alphaR levels were detectable for 8 days following systemic TNFI gene transfer. CIA severity was significantly suppressed by TNFI gene transfer, both prior to and following arthritis onset (P = 0.0001, by repeated-measures 2-factor analysis of variance). Direct synovial TNFI gene transfer was successful, but induced an inflammatory response without any net TNFI benefit. CONCLUSION: Systemic adenoviral-mediated transfer of the TNFI gene suppressed CIA during its transitory expression. Intraarticular gene transfer was limited by an adenoviral synovitis that was not overcome by delivery of the TNFI gene. TNFI is an excellent protein candidate for further therapeutic study.

Adenoviridae↗
PubMed1996

The effect of minocycline in rat models of inflammatory arthritis: correlation of arthritis suppression with enhanced T cell calcium flux.

Adjuvant and collagen arthritis in the rat are widely accepted T-cell-dependent counterparts of rheumatoid arthritis and were used to examine the antiinflammatory properties of minocycline. Administration of oral minocycline, a semisynthetic tetracycline, significantly decreased (P < 0.01) the incidence of arthritis in both models. In vivo exposure to minocycline also significantly increased the percentage of splenocytes exhibiting a rise in free intracellular calcium concentration ([Ca2+]i) following concanavalin A stimulation (P < 0.05 in adjuvant and P < 0.01 in collagen). This enhancement was mitogen dose-dependent and supported exclusively by extracellular Ca2+. Resting [Ca2+]i levels were unaffected by minocycline and predominantly the CD4+ subset was involved. No changes were observed in weight, IgG antibodies to collagen, synoviocyte release of collagenase and prostaglandin E2, acute inflammation in an air-pouch system, or cell surface expression of activation markers (interleukin-2 and transferrin receptors) by splenocytes or lymph node cells. As a controlled [Ca2+]i rise is a critical event in normal T cell activation, minocycline's antiarthritic profile in vivo may relate to perturbed Ca2+ influx during T cell activation, an alteration that could promote the development of clinical tolerance to otherwise arthritogenic stimuli.

Animals↗
PubMed1996

Health status response of rheumatoid arthritis to treatment with DAB486IL-2.

OBJECTIVE: To examine and compare health status and disease activity changes in patients with rheumatoid arthritis (RA) in a clinical trial of the biologic agent DAB486IL-2. METHODS: Data on 45 patients with RA who were enrolled in a multicourse, double-blind trial, consisting of a first, placebo-controlled, course followed by open-label treatment with the active agent to a total of 3 active courses, were examined for evidence of improvement in health status (measured using the 5 components of the Arthritis Impact Measurement Scales 2 [AIMS2]) and disease activity (measured using standard clinical measures and erythrocyte sedimentation rate). RESULTS: Over a single course of treatment, DAB486IL-2-treated patients showed significant improvement relative to placebo-treated patients on the symptom and social components of AIMS2 and in patient's assessment of disease activity. With subsequent open-label courses of treatment with DAB486IL-2, all 5 AIMS2 health status components and the disease activity measures of tender and swollen joint counts, grip strength, and the observer and patient assessments showed steady and generally parallel improvement. CONCLUSION: Short-term health status effects of this biologic agent were detected using the AIMS2.

Activities of Daily Living↗
PubMed1995

Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A double-blind, placebo-controlled trial with open-label extension.

OBJECTIVE: This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA). METHODS: Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as > or = 25% improvement in swollen and tender joints and > or = 25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles. RESULTS: In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nausea/vomiting (50%), elevated (< or = 3 x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients. CONCLUSION: Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.

Adolescent↗
PubMed1993

Effects of oral administration of type II collagen on rheumatoid arthritis.

Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

Administration, Oral↗
PubMed1993

DAB486IL-2 fusion toxin in refractory rheumatoid arthritis.

OBJECTIVE: To evaluate the safety and antiarthritic effects of DAB486IL-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form of the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin-mediated cytotoxicity of activated T cells by inhibition of protein synthesis. METHODS: Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (> or = 50% improved) or meaningful response (> or = 25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. RESULTS: Nine of 19 patients treated with high- or medium-dose DAB486IL-2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti-DT antibodies. CONCLUSION: The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL-2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is required to determine the efficacy of this high-affinity IL-2R-targeted fusion toxin in the treatment of RA.

Adult↗
PubMed1993

Immunotherapy and other novel therapies, including biologic response modifiers, apheresis, and dietary modifications.

Immunologic manipulations under current investigation include various biologic agents and pheresis procedures. Second-generation monoclonal antibodies have been "humanized" to circumvent human anti-mouse antibody production or to carry toxin amplification. At present these studies focus on refractory rheumatoid arthritis and lupus nephritis. Interferons, prostacyclin, and tolerance-inducing or blocking peptides are filling difficult therapeutic niches. Of particular importance are remarkable results for interferon alfa-2b in mastocytosis, and iloprost in Raynaud's disease with digital ulcerations. Enhanced pheresis procedures with photochemotherapy involving psoralens and extracorporeal removal of specific autoantibodies may broaden the spectrum of pheresis applications. Dietary manipulations of fatty-acid intake and caloric restriction have also received attention.

Antibodies, Monoclonal↗
PubMed1993

The correlation of indium-111 joint scans with clinical synovitis in rheumatoid arthritis.

OBJECTIVE: An inflammatory compartment radionuclide such as Indium-111 chloride (111InCl3) may offer advantages over bone seeking radionuclides in the assessment of active rheumatoid synovitis. As an iron analog, 111InCl3 binds iron complexing proteins including transferrin. Active rheumatoid synovitis is a transferrin receptor rich compartment, reflecting profound cellular activation and proliferation. We investigated 111InCl3 scanning for the detection of active rheumatoid arthritis (RA). METHODS: Nine patients satisfying ACR criteria for definite or probable RA were scanned twice at a 28-day interval. Patients were undergoing multiple medication changes with resultant fluctuating disease activity. Blinded readings were performed by an experienced nuclear medicine physician and correlated with simultaneous clinical examinations by a single rheumatologist. Sixteen assessed joint areas/patient and a total of 144 joint areas were available for analysis. RESULTS: Scintigraphy correlated with swollen and tender joint scores at both timepoints. Specificity was highest with stringent scoring. Sensitivity was lowest for small joints with lower 111InCl3 uptake relative to background. A receiver operator curve (ROC), generated to analyze the diagnostic value of varying 111InCl3 scan stringency, demonstrated utilization of the most accurate portion of the ROC curve by the reader. CONCLUSION: 111InCl3 joint scintigraphy correlates with clinically detectable rheumatoid synovitis, supporting the hypothesis that transferrin receptor levels reflect rheumatoid disease activity.

Adult↗
PubMed1991

Misdiagnosis of rheumatoid arthritis in an elderly woman with gout.

Polyarticular gout may be misdiagnosed in the elderly. This reflects the confusing clinical presentation of "diuretic gout" in the elderly, characterized by polyarticular onset, subacute symptoms, hand involvement, and early development of tophi. A misdiagnosis of rheumatoid arthritis can lead to poor treatment of gout, failure to recognize underlying renal insufficiency, and associated cardiac risks. Hyperuricemia may reflect systemic ATP depletion in acutely ill patients and thus represents a predictor for mortality. Medical treatment of polyarticular gout in elderly patients with compromised cardiac and renal function requires recognition of the clinical profile and consideration of the increased toxicity from standard therapies.

Aged↗