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.

Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy.

OBJECTIVE: To conclude observations of efficacy of longterm methotrexate (MTX) treatment of rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA entered a prospective study of MTX in 1983. The study was completed after 132 months of therapy. RESULTS: Significant improvement (p < 0.001) was noted in the number of painful joints, swollen joints, and physician and patient global assessments. There was 50% improvement in the joint pain index and joint swelling index in > 65% of the patients. A significant reduction in prednisone dose was achieved. Sixteen patients withdrew from the study. Toxicity led to 3 drug related withdrawals of study patients (alopecia 1; pneumonitis 2). At 132 months, 10 patients (38%) had completed the study; 3 patients (11%) discontinued due to MTX toxicity. CONCLUSION: MTX was an effective treatment for RA in this 132 month prospective study.

CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study.

OBJECTIVE: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). METHODS: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. RESULTS: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. CONCLUSION: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Lack of a renal-protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin A. Results of a randomized, placebo-controlled trial.

OBJECTIVE: To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. METHODS: In this randomized, placebo-controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 micrograms/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. RESULTS: A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. CONCLUSION: A renal-protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) represents a heterogenous disease characterized by chronic polyarthritis. Most patients with adult RA inherit HLA-DR4 or -DR1 major histocompatibility complex (MHC) genes. While the molecular basis for this genetic predisposition is unknown, the major function of these MHC-encoded molecules is to present peptides to T lymphocytes. It is hypothesized that an endogenous or environmental antigen initiates a MHC-restricted immune response mediated by T lymphocytes, which is followed by a chronic inflammatory reaction involving many cell types. In chronic RA, previous or ongoing antigenic activation might result in detectable skewing of the peripheral alpha/beta T cell receptor (TCR) repertoire. Here we demonstrate a marked expansion of V alpha 12.1-bearing CD8+ T cells in the peripheral blood (mean, 22%; range, 10-43%) of > 15% of RA patients. A major proportion of these patients shared HLA-DQ2 in addition to the expected high frequency DR1 and DR4 alleles. Detailed molecular analysis in three of the RA patients with elevated V alpha 12.1+ T cells identified repeated TCR alpha chain sequences consistent with clonal V alpha 12.1+,CD8+ T cell expansion. In addition to shared TCR V alpha 12.1 germline gene usage among unrelated subjects, a conserved J alpha motif was also detected. Together, these results suggest an antigen-driven mechanism of T cell expansion in these patients and may offer a new approach in examining specific antigen that stimulate T cells in RA.

Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial.

OBJECTIVE: To determine if simultaneously administered low dose leucovorin interferes with the efficacy of methotrexate (MTX). METHODS: An 8-week double blind placebo controlled study of leucovorin (1 mg) in 16 patients with rheumatoid arthritis receiving chronic MTX was performed at a single academic center. RESULTS: A flare of disease activity was not observed. Clinical variables of arthritis activity did not change in the leucovorin treated population. CONCLUSIONS: Low dose leucovorin when taken simultaneously with MTX did not interfere with the efficacy of MTX in a short term 8 week trial.

Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis.

The effects of zileuton, a new 5-lipoxygenase inhibitor, on leukotriene generation and clinical response in rheumatoid arthritis (RA) was studied in a 4-week randomized double blind placebo controlled study at 2 academic rheumatology centers. Zileuton decreased the mean (+/- SEM) ionophore induced synthesis of leukotriene B4 at Week 1 by 70% from 191.2 +/- 28.5 to 57.5 +/- 17.0 ng/ml. A parallel suppression of all major 5-lipoxygenase pathway products was observed. An improvement in clinical variables was observed in the zileuton and placebo treated population. No unique toxicity was identified in this study. Zileuton inhibited 5-lipoxygenase in RA with a suggestion of clinical response with limited toxicity.

Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update.

OBJECTIVE: To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: Eighty-four-month open prospective trial at a single academic rheumatology center. RESULTS: Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity. CONCLUSION: The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.

Disease-modifying agents and experimental treatments of rheumatoid arthritis.

The pharmacologic management of the rheumatoid arthritis (RA) patient involves the use of various classes of therapeutic agents to induce symptomatic relief and reduce disease activity. Aspirin and nonsteroidal antiinflammatory drugs are used initially to lessen the degree of pain and swelling associated with the inflammatory disease process. The addition of a heterogeneous class of compounds, "second-line" therapy (previously known as disease-modifying antiinflammatory rheumatic drugs), is advocated to modify the disease course itself. Second-line treatments include antimalarials, gold salts, D-penicillamine, azathioprine, and methotrexate. Randomized placebo-controlled trials ahve demonstrated the efficacy of these compounds in RA. Improvement in standard parameters of disease activity including the number of painful and swollen joints, duration of morning stiffness, and erythrocyte sedimentation rate has been noted with these second-line drugs. Whether they modify roentgenographic progression is under rigorous study. These agents alone or in combination rarely induce complete disease remission. Therefore, newer therapies are under intensive investigation and include sulfasalazine, cyclosporin A, and combination therapy.

Longterm experience with low dose weekly methotrexate in rheumatoid arthritis.

Longterm prospective studies (several of greater than 5 years' duration) report sustained efficacy with low dose weekly methotrexate. A "steroid-sparing" effect has been noted with methotrexate in 2 of the studies. Of 230 patients enrolled in prospective studies, only 8% stopped therapy due to toxicity and 3% due to lack of efficacy. Life table analysis projected that 63% of these patients would receive therapy for 6 years. Even though adverse experiences were frequent, serious reactions have been rare in the published studies.

Treatment of rheumatoid arthritis.

The management of the rheumatoid patient involves the considered use of pharmacologic agents as therapies to induce symptomatic relief and to reduce disease activity. Aspirin and nonsteroidal antiinflammatory drugs are used initially to lessen the degree of pain and swelling associated with the inflammatory disease process. The aggressive institution of second-line therapy, previously known as disease-modifying antiinflammatory rheumatic drugs, is advocated to modify the disease course itself. These second-line treatments include antimalarials, gold salts, methotrexate, d-penicillamine, and azathioprine. Randomized placebo controlled trials have demonstrated the efficacy of these compounds in this illness. Improvement in standard parameters of disease activity (number of painful and swollen joints, duration of morning stiffness, erythrocyte sedimentation rate) can be related to the therapeutic value of second-line agents. Whether they modify radiographic progression is under rigorous study. Newer therapies under research investigation include sulfasalazine, cyclosporin A, and combination therapy.