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Biomedical subjects

J M Kremer

Publications and source records attributed to J M Kremer.

At least 19 recordsLinked to original sources
PubMed2000

n-3 fatty acid supplements in rheumatoid arthritis.

Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis. In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for > or =12 wk. It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits. These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B(4) from stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process. Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue. n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated.

Animals↗
PubMed1999

Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy.

The traditional "pyramid" or sequential approach to treatment of patients with rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for months to years while seeking to avoid use of second-line antirheumatic drugs until evidence of joint damage was seen. This approach led to short-term reduction of inflammation and a few remissions. However, long-term remissions were rare, and most patients experienced poor long-term outcomes, including joint destruction, severe functional declines, considerable economic losses, work disability, and premature mortality. At this time, a "preventive" strategy is evolving in which early aggressive treatment with disease-modifying antirheumatic drugs is used, seeking to minimize long-term joint damage. When residual inflammation remains after maximum doses of single agents, as is usually the case, combinations of disease-modifying antirheumatic drugs appear to be a reasonable consideration for many patients. Methotrexate is the most commonly used "anchor drug" in combination therapy. Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (and often lower) toxicity for combinations of methotrexate plus cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and infliximab. Further studies lasting 5 years or more are needed to determine the long-term effectiveness, toxicities, and optimal clinical use of disease-modifying antirheumatic drug combinations. At this time, such combinations are taken by at least some patients under care of almost all rheumatologists, and it appears likely that they will be used increasingly in the coming decades.

Antirheumatic Agents↗
PubMed1999

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.

BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept. CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.

Adult↗
PubMed1999

Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis.

OBJECTIVE: To examine the safety and pharmacokinetics of and clinical response to leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to patients with active rheumatoid arthritis (RA) who have been receiving long-term methotrexate therapy. METHODS: This was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17+/-4 mg/week (mean +/- SD) for > or =6 months were given leflunomide, 10-20 mg/day. Patients were assessed for adverse effects, pharmacokinetic measurements of leflunomide and methotrexate, and clinical response by American College of Rheumatology (ACR) 20% response criteria. RESULTS: Twenty-three patients completed 1 year of treatment. No significant pharmacokinetic interactions between leflunomide and methotrexate were noted. This combination therapy was generally well tolerated clinically, with the exception of elevations of liver enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals were voluntary, 3 were due to persistent elevation of plasma transaminase levels, and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20% response criteria. Two met ACR criteria for remission after 1 year. CONCLUSION: The combination of methotrexate and leflunomide has therapeutic potential in RA.

Adult↗
PubMed1999

The psychosocial effects of rheumatoid arthritis on the patient and the well partner.

Rheumatoid arthritis (RA) is a chronic disorder that can have a severe impact on patient's lives. This present study investigated four questions regarding the psychosocial effects on patients and their well partners. First we found that depression for both patients and partners were slightly elevated and 35.7% of patients and 23.3% of well partners had scores above the cut-off for possible clinical depression on the Center for Epidemiological Studies Depression Scale. Second, there was no significant difference between the patients' level of distress and that of the partners. Third, there were moderate positive correlations between patients' and partners' scores on measure of psychological functioning. Fourth, there were no differences in either the patients' or partners' well-being based on the gender of the patient. Finally, an exploratory analysis was conducted to examine the factors which influence the patients' and partners' depression and their view of the relationship.

Adaptation, Psychological↗
PubMed1999

Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis.

OBJECTIVES: Methotrexate is currently one of the most widely prescribed disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs increases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination therapy with methotrexate. This review compares the mode of action of methotrexate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination. METHODS: A literature review of the biochemical mechanisms considered to be the basis for the therapeutic efficacy of methotrexate and leflunomide in treating RA is presented. RESULTS: Low-dose methotrexate inhibits cytokine production, purine biosynthesis, and, in an animal model, causes the release of adenosine, a potent antiinflammatory agent. Leflunomide, through inhibition of de novo pyrimidine biosynthesis, can regulate lymphocyte proliferation. CONCLUSIONS: The biochemical mechanisms underlying the therapeutic efficacy of low-dose methotrexate and leflunomide in the treatment of RA are quite different. The potentially complementary mechanisms of action of these two effective DMARDs should provide a rationale for their use in combination therapy for patients whose condition no longer responds to methotrexate alone.

Adenosine↗
PubMed1999

Leflunomide for the treatment of rheumatoid arthritis.

Leflunomide treatment appears to offer an alternative to methotrexate and sulfasalazine and is a welcome addition to the therapeutic armamentarium for treating active RA. Leflunomide treatment for more than 12 months results in clinically meaningful improvements in disease-specific measures of physical function. The phase 3 trials have shown leflunomide to be as effective as methotrexate and sulfasalazine and an option for initial DMARD therapy. As with all new agents, the long-term safety and value of leflunomide will be determined by use in the clinic.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. METHODS: Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 microg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for > or = 30% reduction in both swollen and tender joint counts. RESULTS: Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 microg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 microg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. CONCLUSION: Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Administration, Oral↗
PubMed1998

Methotrexate and emerging therapies.

It is likely that all new therapeutic interventions will be used with methotrexate in combination therapy. These combinations may yield real therapeutic advances. The potential for end organ toxicity, opportunistic infection, and malignancy will need to be carefully monitored with long-term, meticulously conducted observational studies. Expense, ease of use, and perceived benefit-to-risk ratio will determine which new agents become most commonly prescribed with methotrexate.

Antirheumatic Agents↗
PubMed1997

Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group.

BACKGROUND: Toxicity limits the use of methotrexate. OBJECTIVE: To identify risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. DESIGN: Case-control study. SETTING: One private and five academic rheumatology practices. PARTICIPANTS: Methotrexate recipients with rheumatoid arthritis with and without lung injury. MEASUREMENTS: Potential risk factors examined were sociodemographic and lifestyle characteristics, medical history, clinical and ancillary features and treatment of rheumatoid arthritis before methotrexate therapy, and characteristics of methotrexate therapy. Cases of lung injury were defined according to the modified criteria of Searles and McKendry. RESULTS: Ninety-four percent of the study participants were white, and 67% were women. Case-patients (n = 29) were older than controls (n = 82) (61.5 compared with 54.5 years of age). The strongest predictors of lung injury, after adjustment for other variables, were older age (odds ratio [OR], 5.1 [95% CI, 1.2 to 21.1]), diabetes (OR, 35.6 [CI, 1.3 to infinity]), rheumatoid pleuropulmonary involvement (OR, 7.1 [CI, 1.1 to 45.4]), previous use of disease-modifying antirheumatic drugs (OR, 5.6 [CI, 1.2 to 27.0]), and hypoalbuminemia (OR, 19.5 [CI, 3.5 to 109.7]). Previous use of disease-modifying antirheumatic drugs and hypoalbuminemia had very large attributable risks. CONCLUSION: Knowledge of the risk factors that predispose patients with rheumatoid arthritis to the toxic effects of methotrexate on the lung may provide a rationale for monitoring high-risk patients and may facilitate their management.

Antirheumatic Agents↗
PubMed1997

Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review.

OBJECTIVE: To describe the clinical, laboratory, radiologic, and histopathologic features of methotrexate (MTX)-induced lung injury in a combined cohort of selected patients with rheumatoid arthritis (RA) and all cases reported in the English-language literature. METHODS: Retrospective combined cohort review and abstraction from the medical literature. Case reports were obtained from 6 centers that had 4 or more cases of potential MTX lung injury per site. RA patients who were seen between 1981 and 1993 and who satisfied predetermined criteria for the presence of MTX lung injury were identified. RESULTS: Twenty-seven patients satisfied the criteria for definite MTX lung injury, and 2 for probable MTX lung injury. Predominant clinical features of MTX lung injury included shortness of breath in 27 patients (93.1%), which was present for 23.5 +/- 22.3 days (mean +/- SD), cough in 24 (82.8%), present for 26.9 +/- 28.5 days, and fever in 20 (69.0%), present for 10.4 +/- 12.8 days. Five patients (17.2%) died, compared with 12 of 68 (17.6%) reported in the medical literature. Four of the 6 patients who were re-treated with MTX after an initial pulmonary event developed recurrent lung toxicity, resulting in 2 deaths, compared with a recurrence rate of 3 of 6 in the literature. CONCLUSION: MTX lung injury is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be re-treated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome that has been observed in this and other studies.

Aged↗
PubMed1997

Xanthomatous infiltration of ankle tendons.

We present a case of type II hyperbetalipoproteinemia in a patient whose diagnosis had been previously unrecognized, and who had previously been misdiagnosed with rheumatoid arthritis and later gout. Radiographic and MR imaging features of the patient's ankles were pronounced but otherwise typical of xanthomatous infiltration. Radiologic assessment can be useful in permitting a specific diagnosis to be made in patients with periarticular and tendinous swelling.

Ankle↗
PubMed1997

Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis.

In order to compare the relative bioavailability of orally administered methotrexate (MTX) with i.m. administration in patients with rheumatoid arthritis, we compared the pharmacokinetics of MTX at both the usual starting dose of 7.5 mg and at higher established maintenance dosages in 21 patients. Pharmacokinetic measures were repeated approximately 6 and 18 months after baseline while patients consumed their usual maintenance doses of MTX (17.0 +/- 3.8 mg). The relative bioavailability of the usual maintenance dose of MTX was reduced by 13.5% compared with the initial dose of 7.5 mg (P = 0.026). Area under the serum concentration vs time curve (AUC) was significantly reduced with oral vs i.m. administration at usual maintenance doses (decrease of 0.729 mumol.h/l by oral administration, P = 0.027), but not at a 7.5 mg dose of MTX. Clinicians using MTX should not assume constant and complete bioavailability across the dose range used to treat patients with rheumatoid arthritis. Our observations explain the reported clinical success of switching from an oral to a parenteral route of administration in patients receiving maintenance doses of MTX.

Administration, Oral↗