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Biomedical subjects

L W Moreland

Publications and source records attributed to L W Moreland.

At least 19 recordsLinked to original sources
PubMed2005

Methotrexate dosage reduction in patients with rheumatoid arthritis beginning therapy with infliximab: the Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) trial.

OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.

Adolescent↗
PubMed2004

A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.

OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.

Antirheumatic Agents↗
PubMed2004

Genetic risk factors for infection in patients with early rheumatoid arthritis.

We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038). Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.

Age Factors↗
PubMed2002

Immune function in patients with rheumatoid arthritis treated with etanercept.

Etanercept, a recombinant human tumor necrosis factor (TNF) inhibitor that binds both soluble and cell-bound TNF, has been shown to reduce disease activity and inhibit joint destruction when administered to patients with rheumatoid arthritis (RA). Because TNF receptors are found on many types of cells that modulate the immune response, we evaluated the general immune function of a subset of RA patients in a blinded clinical study. No significant differences were seen between patients treated with etanercept or placebo in the surface antigen phenotypes of peripheral blood leukocytes, T cell proliferative responses, neutrophil function, delayed-type hypersensitivity (DTH) reactions, serum immunoglobulin levels, or incidence of infections. Although this observational study was relatively small and could detect only major changes in immunological status, the stability of immune function over time in patients receiving etanercept corroborates the findings in clinical studies, which suggest that etanercept does not alter overall global immune function.

Adult↗
PubMed2001

Potential biologic agents for treating rheumatoid arthritis.

The encouraging clinical results observed in trials using anti-TNF therapy clearly warrant further studies to determine whether TNF inhibitors are capable of modifying the destructive component of this disease in long-term follow-up studies as well as to assess the safety of long-term use (see the article by Keystone in this issue). It is also reasonable to propose that interfering with the cytokine cascade earlier in the course of disease may be of even greater therapeutic benefit. As the pathogenetic mechanisms in RA are more clearly defined, especially in early disease and in those individuals destined to develop severe disease, the potential of other biologic agents to specifically inhibit these critical pathways may provide better treatments for our patients. Many potential targets in the immune-mediated process of RA are currently being rigorously evaluated in clinical trials. Use of combinations of biologic therapies, perhaps in human patients with RA, should be of considerable interest in future trials.

Arthritis, Rheumatoid↗
PubMed2001

Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC Study Group.

A prospective, multicenter, randomized, double-blind, controlled trial was conducted in 226 patients with knee osteoarthritis to evaluate the safety and efficacy of intraarticular injections of sodium hyaluronate. Patients were randomized to three weekly injections of 30 mg sodium hyaluronate or physiologic saline (control) and were observed for an additional 25 weeks. In comparison with the control group, among patients who completed at least 15 weeks of the study and whose Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was less than 12 at baseline, sodium hyaluronate injection resulted in improvement in Western Ontario and McMaster Universities Osteoarthritis Index pain score, patient and investigator global assessments, and pain on standing from Weeks 7 to 27. Fifty-eight percent of patients treated with sodium hyaluronate achieved a 5-unit or greater improvement in mean pain score from Weeks 7 through 27, compared with 40% of control patients. In addition, nearly twice as many patients treated with sodium hyaluronate as with saline (30% versus 17%, respectively) achieved a net improvement of at least 7 units. In contrast to treatment with saline, Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was inversely related to the magnitude of improvement after treatment with sodium hyaluronate. Few side effects were attributed to treatment, and no differences between treatment groups were seen in this respect (sodium hyaluronate, nine [8%]; saline, 11 [10%]). The incidence of injection site reactions was low (sodium hyaluronate, 1.2 %; saline, 1.5%). The results indicate that sodium hyaluronate treatment is well tolerated and produces statistically and clinically significant improvement of symptoms in patients with mild to moderate knee osteoarthritis in whom pain in the contralateral knee is relatively modest.

Adjuvants, Immunologic↗
PubMed2001

TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept.

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.

Animals↗
PubMed2001

A clinical and economic review of disease-modifying antirheumatic drugs.

Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Antirheumatic Agents↗
PubMed2001

New therapeutic approaches to the management of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common disease that affects up to 1% of the population, and causes significant morbidity and early mortality. The aetiology of RA is unknown; however, in the last 10 to 15 years significant advances in molecular technology have provided a greater understanding of the pathogenesis of the disease. This has led to the development of new approaches to the treatment of RA. The disease modifying antirheumatic oral agent leflunomide inhibits the proliferation of activated T cells that are important in the inflammation and degradation of synovial tissues. The 2 biological agents approved for the treatment of RA, infliximab and etanercept, are inhibitors of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha). Infliximab is a chimeric human/mouse monoclonal antibody which is administered by intravenous infusion and binds with high affinity to TNFalpha, thereby neutralising its effects. Etanercept is a recombinant, soluble TNF receptor molecule which is administered subcutaneously and binds to TNFalpha in the serum rendering it biologically inactive. The protein A immunoadsorption column is a medical device that in conjunction with plasmapheresis can be used in patients with refractory RA. These agents have provided new and effective therapies for the treatment of patients with RA.

Antibodies, Monoclonal↗
PubMed2001

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Adolescent↗
PubMed2001

Management of rheumatoid arthritis: the historical context.

We review the historical highlights of the management of rheumatoid arthritis (RA). Studies of nonsteroidal antiinflammatory drugs, disease modifying antirheumatic drugs, and biological agents over 5 decades were evaluated and summarized. There is emphasis on drug therapy as it has developed and evolved from empirical relief of symptoms with salicylates to targeted intervention in the immunoinflammatory process with tumor necrosis factor inhibitors. A therapeutic paradigm has been proposed to rationalize the use of the available therapies. If one accepts the thesis that both the acute and chronic consequences of RA are due to persistent misdirected and inadequately controlled inflammation that causes tissue destruction and loss of function, then prolonged complete control of the abnormal inflammatory process is the fundamental first step in the management of all patients with RA. Unfortunately, even with the newest therapeutic options to treat RA, most patients achieve only partial suppression of inflammation and many lose therapeutic benefit after an initial good response. The management of persistent or recurrent rheumatoid inflammation and disability continues to be a challenge. It remains to be determined whether the future addition of more potent specific interventions in the immunoinflammatory process will be able to solve this problem without disarming host defenses against infections and tumors.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Tumor necrosis factor inhibitors: new options for treating rheumatoid arthritis.

There is accumulating evidence that tumor necrosis factor plays a major role in the pathogenesis of rheumatoid arthritis. Recent biotechnological advances have allowed for the development of agents that directly target TNF, a proinflammatory cytokine. In the last 2 years, the U.S. Food and Drug Administration and the European Union's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of immunoglobulin G1 and the extracellular domain of a TNF receptor (p75). Infliximab is a chimeric monoclonal antibody composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well tolerated in RA patients.

Animals↗
PubMed2000

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Administration, Oral↗
PubMed2000

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

Adolescent↗
PubMed2000

Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo.

OBJECTIVE: To compare the functional status and well-being of patients with rheumatoid arthritis (RA) who were randomly assigned to receive placebo, etanercept 10 mg, or etanercept 25 mg during a 26-week, phase III, double-blind clinical trial. BACKGROUND: No single indicator of disease activity, severity, or therapeutic efficacy has been established for RA. During the past decade, health-related quality of life, a multidimensional way to assess physical, emotional, and social aspects of a disease or its treatment, has become an important outcome in RA studies and in assessments of RA drug therapies. METHODS: A total of 234 patients completed the Health Assessment Questionnaire (HAQ), the Short-Form 36 (SF-36) (n = 48 patients), items assessing energy and mental health from the Medical Outcomes Study (MOS), and a single-item rating scale assessing current health (feeling thermometer) at baseline and several times during 6 months. RESULTS: Significant improvements from baseline to last assessment were reported with etanercept versus placebo and in the HAQ Disability Index score (ie, the total HAQ score) and all 8 HAQ categories (P < 0.05), with the exception of grip. Significant improvements with etanercept in the MOS energy and mental health subscales, current health (from the feeling thermometer), and mental and physical function components of the SF-36 were reported (P < 0.05). CONCLUSIONS: Patients receiving 10- or 25-mg doses of etanercept reported significantly better functional status and well-being than did patients receiving placebo.

Adult↗