Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 10367688 | Animal models of arthritis: relevance to human disease. | 1999 Jan | Animal models of arthritis are used to evaluate potential antiarthritis drugs for clinical use. Therefore capacity of the model to predict efficacy in human disease is one of the most important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability include rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis, and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged periods would preclude dosing in humans at levels that might provide disease-modifying effects. Animal models of osteoarthritis (OA) include mouse and guinea pig spontaneous OA, meniscectomy and ligament transection in guinea pigs, meniscectomy in rabbits, and meniscectomy and cruciate transection in dogs. None of these models have a proven track record of predictability in human disease because there are no agents that have been proven to provide anything other than symptomatic relief in human OA. Efficacy data and features of the various models of RA and OA are discussed with emphasis on their proven relevance to human disease. | |
| 10381034 | Effects of interleukin 1 receptor antagonist alone and in combination with methotrexate in | 1999 Jun | OBJECTIVE: To determine the benefit of combination treatment with the interleukin 1 receptor antagonist (IL-1ra) and methotrexate (MTX) in adjuvant arthritic rats. METHODS: Rats with adjuvant arthritis were treated by continuous sc infusion with IL-1ra (5 mg/kg/h). Effects of IL-1ra treatment alone were compared to treatment with daily oral MTX (0.048, 0.06, or 0.075 mg/kg) or MTX in combination with IL-1ra. Efficacy was monitored by sequential caliper measurement of ankle joints, final paw weights, and histologic evaluation with particular emphasis on bone lesions. RESULTS: Treatment with IL-1ra alone resulted in 6% inhibition of paw swelling assessed by final paw weight. Treatment with MTX (0.075 mg/kg PO) gave 47% inhibition and the combination resulted in an 84% decrease in swelling. Histologic evaluation of ankle joints revealed 53% inhibition of bone resorption with IL-1ra alone, 58% inhibition with MTX alone, and 97% inhibition in combination treated rats. Lower doses of MTX in combination with IL-1ra also provided additive benefit on arthritis variables. CONCLUSION: Combination therapy with IL-1ra and MTX results in additive or synergistic benefit, with excellent inhibition of all arthritis variables. These data support clinical investigation of the use of combination therapy of IL-1ra and MTX in patients with rheumatoid arthritis. | |
| 11268332 | Autologous bone marrow transplantation versus alternative drugs in pediatric rheumatic dis | 2000 Nov | A minority of children suffering from severe rheumatic diseases are unresponsive to conventional treatments. These patients can now be managed with a variety of immunosuppressive therapies. Methotrexate is considered the first choice disease-modifying agent for adult and juvenile rheumatoid arthritis. In patients unresponsive to low doses of methotrexate, medium or high-doses can be useful. Instead of methotrexate, a recently developed immunosuppressive drug, mycophenolate-mofetil, which inhibits T- and B-lymphocyte proliferation, can be used. Another possibility for refractory rheumatic diseases, with no increase in toxicity, is combination therapy, for example methotrexate plus cyclosporine, or methotrexate plus salazopyrine or intravenous pulses of cyclophosphamide and methylprednisone. More recently two distinct inhibitors of tumor necrosis factor (etanercept and infliximab have been used successfully for intractable rheumatic diseases (juvenile idiopathic arthritis, psoriatic arthritis, spondyloarthropathies) but the follow-up is still too short to establish their long-term effectiveness. If all these treatments are unsuccessful, an autologous bone marrow transplantation can be proposed to selected patients. Interesting results have been obtained in pediatric rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus and systemic sclerosis. Further studies are required to assess the best procedures able to induce remission with a minimal risk of fatal events. | |
| 17039159 | Current medication choices in juvenile rheumatoid arthritis II--update of a survey perform | 2001 Oct | The documentation of treatments used for Juvenile Rheumatoid Arthritis (JRA) is important to allow for the evaluation of practice patterns for future outcome studies. A survey of nine pediatric rheumatologists was performed between September 1999 and February 2000. Each of the physicians prospectively recorded demographic and treatment information on consecutively sampled JRA patients (n=395). Pauciarticular onset JRA was present in 46%, polyarticular onset JRA in 35%, and systemic onset JRA in 19% of the children. Naproxen was the most frequently prescribed medication (55% of the patients), followed by methotrexate (MTX), which was used in 39% of the patients. Folic acid supplementation (1 mg/day) was provided to 69% of the patients treated with MTX. Etanercept was used in 11% of the children. Eleven percent of the patients received corticosteroids, and 13% of children on corticosteroids took calcium supplements. Uveitis was present in 8% and had a chronic course in 79% of those cases. Although systemic medications were used in 50% of the children with uveitis to control eye inflammation, severe damage to the eyes developed in 30% of them. Fourteen percent of the patients required gastroprotective medications. Compared with findings of a similar survey performed in 1993, there was no significant change in the frequency of use of naproxen, but nabumetone is now more often prescribed, and COX-2 inhibitors have been introduced in the therapy of JRA. Changes among second-line agents used for JRA have also occurred, although there was no change in the frequency of use of MTX or corticosteroids. JRA continues to be a treatment challenge for the practicing pediatric rheumatologist. Patients often show incomplete response to the currently available medications. Therefore, new therapeutic agents need to be evaluated for their use in JRA, and the treatment of JRA associated uveitis especially needs to be improved. | |
| 11037077 | A family physician's guide to monitoring methotrexate. | 2000 Oct 1 | Methotrexate has a long history of use in the treatment of various immunologic diseases, including rheumatoid arthritis and psoriasis. Although the drug is usually prescribed by a subspecialist, a family physician may assume responsibility for monitoring methotrexate therapy. Major toxic effects, such as hepatic, pulmonary, renal and bone marrow abnormalities, require careful monitoring. Minor toxic effects, such as stomatitis, malaise, nausea, diarrhea, headaches and mild alopecia, are common but respond to folate supplementation. Methotrexate is administered once weekly as a single dose or in divided doses given over a 24-hour period. To reduce the incidence of major toxic effects, methotrexate should never be given in daily doses. Relative contraindications include renal dysfunction, liver disease, active infectious disease and excessive alcohol consumption. Both women and men of reproductive age should use birth control during methotrexate therapy. Potential drug interactions include salicylates and nonsteroidal anti-inflammatory drugs, which are both commonly used in patients with rheumatoid arthritis or psoriasis. A premethotrexate evaluation is important to ensure proper patient selection for this effective but potentially toxic drug. | |
| 24383564 | Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid | 2000 Jun | Abstract The objective of this study was to evaluate the efficacy and safety of an additive combination of a disease-modifying antirheumatic drug (DMARD) actarit and low-dose methotrexate (MTX) in patients with active rheumatoid arthritis (RA) unresponsive to MTX. Thirty-four patients with active RA, who had been unsuccessfully treated with MTX for at least 3 months were enrolled on a 24-week course of actarit (300 mg/day) and MTX (2.5-10 mg/week). Disease activity was evaluated by physical global assessments using conventional measures (Japan Rheumatism Association), and the American College of Rheumatology (ACR) criteria of improvements in RA. Thirty-two patients completed this study. No severe adverse drug reactions were seen. Patients whose RA did not respond to MTX alone responded to the combination therapy, with a significant improvement in the duration of morning stiffness, grip strength, swollen joint counts, patient's articular pain score, modified health assessment questionnaire (M-HAQ) score, score of both patient's and physician's global assessments, and C-reactive proteins (CRP). Sixteen patients (50.0%) and 9 patients (31.0%) showed a significant improvement in overall conventional measures, and ACR response criteria, respectively, and 60.0% of RA patients who received MTX for more than 1 year showed improvement in ACR definition. Patients who responded to the combination treatment within the first 12 weeks showed persistent improvement for the remaining part of the 24 week period. Our results indicate that the additive combination of actarit and MTX is safe, and without serious adverse effects, and has an excellent efficacy in patients with active and refractory RA. | |
| 9987950 | [Institute of Rheumatology and progress of antirheumatic therapy]. | 1998 | The paper deals with the achievements of the Institute of Rheumatology in antirheumatic therapy, among them there are methods of objective assessment of antirheumatic drugs, the first use of antimalarials in the treatment of chronic rheumatic fever, discovery of immunodepressive properties of these drugs, specification of the mechanism of action of several NSAIDs. Antilymphocytic globulin, salazopyridazine and the alkylating drug dopan were used for the first time in therapy of rheumatic diseases. Administration of the most potent NSAIDs diclofenac or indomethacin to patients with acute rheumatic fever proved to be as effective as prednizolone. Special attention is paid to the combination treatment of rheumatoid arthritis with NSAIDs. The concurrent administration of aurannofin and methotrexate was shown to cause a more rapid development of clinical improvement than monotherapy with either drug. A combination of gold aurothiomalate and hydroxychloroquine and that of low doses of D-penicillamine and cyclophosphamide had no advantages over monotherapy. Revealing the therapeutical potential of antibodies to interferon-gamma in the treatment of rheumatic arthritis and psoriatic arthritis was the most important achievement of recent years. These studies open new vistas for anticytokine treatment of rheumatic diseases. | |
| 9435395 | [Aminotransferase levels in rheumatoid arthritis patients treated with methotrexate]. | 1997 Mar | Increase of the aminotransferase levels in 53 patients treated with methotrexate (MTX) were analysed in a retrospective study. The mean dose of MTX was 7.46 mg/week (range 2.5-15 mg) during at least 30 weeks (mean time of MTX use 124 weeks). The aminotransferase levels were transitorily increased in 13 patients, always less than three times the upper limit of normal. Only in three patients the AST and ALT levels were persistently increased and lead to the drug discontinuation in two cases. These results showed that increase of aminotransferases was a frequent observation (24.5%) during the first two-three years of follow-up, without interference in the overall clinical management. | |
| 11525955 | Cutaneous ulceration as a sign of methotrexate toxicity. | 2001 Sep | Methotrexate (MTX) inhibits DNA synthesis by competition with dihydrofolate reductase. Adverse cutaneous reactions to MTX are usually dose-related and have been mainly reported in patients receiving extremely large doses of chemotherapy. Painful erosion of psoriatic plaques has been often reported as an early sign of MTX toxicity, but cutaneous ulceration as a sign of MTX toxicity in patients without psoriasis has only been described in one case. We report a patient with rheumatoid arthritis and without psoriasis who developed cutaneous ulceration on the knuckles as a sign of MTX toxicity. Cutaneous ulceration by MTX toxicity is an exclusion diagnosis and its pathogenic mechanism may be multifactorial, including direct toxicity of the drug in addition to local factors. | |
| 11791648 | Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low | 2001 Nov | OBJECTIVES: To analyse pulmonary toxicity in psoriatic arthritis patients treated with weekly low-dose methotrexate. METHODS: A transversal study was carried out to analyse the findings on chest x-rays and high resolution computed tomography, and the results of pulmonary function tests in 27 Caucasian psoriatic arthritis patients treated with weekly low-dose methotrexate. None of them had previous recognized interstitial lung disease. RESULTS: The median age of the patient cohort was 50 years (range 24-70 years) and the sex ratio was 20M/7F. 17 patients had previously used other disease-modifying antirheumatic drugs. The mean weekly dose of methotrexate was 8.46 mg (range 5-15 mg), the average treatment period was 52 months (range 3-240 months), and the median cumulative dose was 2241 mg (range 300-6520 mg). High resolution computed tomography failed to show alveolar or interstitial involvement in any patient. Diffusing lung capacity for carbon monoxide was mildly altered only in 2 cases. Pulmonary function tests did not show differences between patients with and without recognized risk factors for developing methotrexate-associated lung toxicity identified in rheumatoid arthritis patients (old age, diabetes, hypoalbuminemia, previous use of disease modifying antirheumatic drugs). CONCLUSION: In this cohort of 27 psoriatic arthritis patients methotrexate was not associated with pulmonary fibrosis evaluated by means of sensitive imaging findings and pulmonary function tests. | |
| 10493688 | Current treatment by United States and Canadian pediatric rheumatologists. | 1999 Sep | OBJECTIVE: To determine current treatment practices for 11 selected pediatric rheumatic diseases. METHODS: A questionnaire was mailed to 224 US and Canadian physicians who were listed in membership directories that included pediatric rheumatologists. RESULTS: One hundred seventy-four questionnaires (78%) were returned. Board certified pediatricians accounted for 86% of respondents. Nonsteroidal antiinflammatory drugs were the most commonly used medicines for all forms of juvenile rheumatoid arthritis (JRA), seronegative enthesopathy and arthropathy syndrome (SEA), and Henoch-Schönlein purpura, whereas oral corticosteroids were most frequently used for systemic lupus erythematosus (SLE), juvenile dermatomyositis, polyarteritis nodosa, and sarcoidosis. Intraarticular corticosteroid injection was the second most common therapy for pauciarticular JRA, but methotrexate (MTX) was second for polyarticular and systemic onset forms of JRA, and sulfasalazine was second for SEA. For all diseases, MTX was administered orally roughly twice as often as subcutaneously. In treating SLE, cyclophosphamide was used more frequently than azathioprine, cyclosporin A, or intravenous immunoglobulin. CONCLUSION: The results from this survey should allow individual practitioners to compare their treatment patterns to pediatric rheumatologists in the US and Canada as a whole. | |
| 10855951 | Effects of methotrexate on nucleotide pools in normal human T cells and the CEM T cell lin | 2000 | It has been proposed that the clinical utility of methotrexate (MTX) in the treatment of rheumatoid arthritis may be due, in part, to inhibition of 5-amino imidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT) by polyglutamated forms of MTX. AICARFT is the second folate dependent enzyme in de novo purine biosynthesis. In this study, the effects of MTX on de novo purine biosynthesis as well as total nucleotide pools were evaluated in both the human T cell line, CEM, and phytohemagglutinin-activated normal human T lymphocytes. De novo synthesized purines were metabolically labeled with 14C-glycine after MTX treatment and analyzed by HPLC. In normal T cells, MTX produced a dose-dependent reduction in de novo adenosine and guanosine pools with maximal effects (>50%) at 1 microM MTX. In CEM cells, de novo purine synthesis was almost completely blocked by 1 microM MTX. Total purine pools were also reduced in both cell types after MTX treatment. Since 1 microM MTX caused almost complete growth inhibition in CEM cells, we evaluated whether growth could be reconstituted with exogenous purine bases and pyrimidine nucleosides which can be utilized via salvage pathways. The combination of hypoxanthine and thymidine substantially reversed growth inhibition with 1 microM MTX in CEM cells. Taken together, these results demonstrate that MTX inhibits de novo nucleotide synthesis in T cells and suggest that AICARFT inhibition may be one aspect of the multi-site mechanism of MTX action in the treatment of rheumatoid arthritis. | |
| 10325668 | Granisetron (Kytril) suppresses methotrexate-induced nausea and vomiting among patients wi | 1999 Mar | OBJECTIVE: Methotrexate (MTX) is an increasingly popular anti-rheumatic drug with its usefulness limited by toxicity, most commonly gastrointestinal (GI). The aim of the study was to study the effectiveness of the 5-HT3 receptor antagonist granisetron (GR) in the therapy of MTX-induced nausea. METHODS: A single-blind 8 week pilot study with random allocation to either GR 1 mg or prochlorperazine (Stemetil; PCh) 10 mg was undertaken in 13 patients who were taking or had taken MTX for either rheumatoid arthritis (10) or psoriatic arthritis (3). RESULTS: One in six patients treated with PCh completed the 8 week study compared to 7/7 treated with GR. After switching of symptomatic patients, 11 completed the study on GR and median improvement was by two grades (P < 0.001) with a significantly better visual analogue scale score for patient satisfaction compared to PCh. CONCLUSION: Treatment with GR may be useful in establishing and maintaining some patients on MTX where GI toxicity would have precluded such therapy. | |
| 10920689 | [Rapidly progressed secondary amyloidosis in a patient with Still's disease with gamma-all | 2000 Jun | A fifteen-year-old boy was admitted to our hospital because of lower abdominal pain, watery diarrhea and mucobloody stool. Two years before admission, he was diagnosed to have Still's disease presenting with polyarthritis, sore throat, remittent fever and typical skin rash. He had been treated with non-steroidal anti-inflammatory agents, oral prednisolone and low-dose methotrexate. Although he was almost free of symptoms during the next two years, serum C-reactive protein (CRP) levels continued to be elevated moderately. He began to complain of lower abdominal pain and loose stool in May 1997 and came down with mucous-bloody diarrhea in June. Laboratory data on admission showed an elevated level of serum CRP (13.9 mg/dl). The biopsy of the stomach, ileum, sigmoid colon and rectum revealed the deposition of amyloid protein of AA type, which confirmed the diagnosis of secondary amyloidosis. The dose of prednisolone was increased and dimethyl sulfoxide per os or rectum was instituted, which improved his gastro-intestinal symptoms to some extent. However, fever, arthritis and diarrhea recurred along with tapered prednisolone dosage. In addition to gastro-intestinal symptoms, arrhythmia and proteinuria appeared. These symptoms were considered to reflect general deposition of amyloid in his body. He is now on immunosuppressive agent and high-dose prednisolone. Several studies report the higher frequency of gamma-allele of SAA 1 gene in the cases of rheumatoid arthritis with AA-amyloidosis than in those without. In the patient presented here, molecular biological analysis revealed that his SAA 1 gene was composed of beta- and gamma-allele. The presence of gamma-allele in his SAA 1 gene might be one of the factors that predisposed him for generalized deposition of amyloid protein in such a short period of time. | |
| 9933419 | Methotrexate specifically modulates cytokine production by T cells and macrophages in muri | 1999 Jan | Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-gamma) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-gamma production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-alpha production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA. | |
| 17039083 | Early onset methotrexate-induced pancytopenia and response to G-CSF: a report of two cases | 2001 Feb | Methotrexate (MTX) is one of the most widely used antirheumatic drugs for the treatment of rheumatoid arthritis. Whereas the hepatotoxicity of methotrexate is well recognized, the hematologic toxicity, namely, pancytopenia, is still a concern and is potentially fatal. We report two cases of early-onset methotrexate-induced pancytopenia that were successfully treated with granulocyte colony-stimulating factor (G-CSF). The pancytopenia improved with 3 days of administration. A review of the literature revealed at least 146 reported cases of MTX-induced pancytopenia. Significant risk factors for myelotoxicity included renal impairment, infection, and hypoalbuminemia. Successful management includes prompt discontinuation of MTX, intravenous folinic acid, high-dose steroids and, as in our case, G-CSF. | |
| 9692314 | Necrotizing fasciitis complicating disseminated cutaneous herpes zoster. | 1998 Mar | The association of necrotizing fasciitis, often due to group A streptococcus and primary varicella (chicken pox), is unusual but recognized in children. The association in adults is rare but one report in the literature describes a previously healthy man with the two disorders. We now describe a case of disseminated cutaneous herpes zoster complicated by subacute necrotizing fasciitis in an elderly woman taking low dose methotrexate and prednisone for rheumatoid arthritis. Staphylococcus aureus was isolated. Localized debridement and split skin grafting were required. | |
| 12793958 | Combination of methotrexate and prednizone decreases circulating concentrations of interle | 1999 Jan | OBJECTIVE: To evaluate the effect of methotrexate (MTX) in combination with prednizone on cytokine levels, acute phase proteins and thiobarbituric acid reactive substances (TBAR--an indicator of peroxidative damage to tissue lipids) in the blood of rheumatoid arthritis (RA) patients and to investigate their associations with clinical disease activity. METHODS: We measured blood concentrations of interleukin-1 beta (IL-1 beta), interleukin- 6 (IL-6), TBARs and classical clinical and laboratory indices of disease activity in 36 RA subjects before and after 3 and 6 month treatment with MTX and prednizone. Only RA subjects who stopped any disease-modifying anti rheumatic drugs treatment for last 3 months were included in the study. Baseline cytokine and TBARs levels were compared with those obtained with 20 healthy controls. RESULTS: Compared to controls RA subjects had elevated levels of circulating IL-1 beta (63.3 +/- 47.6 vs 13.7 +/- 7.8 pg/ml, p<0.01), IL-6 (147.2 +/- 76.5 vs 15.9 +/- 13.3 pg/ml, p<0.001) and TBARs (3.11 +/- 0.42 vs 1.34 +/- 0.45 nmol/1, p<0.001) concentrations. MTX in combination with prednizone improved patient clinical status that was accompanied by 1.96-, 1.25-, and 1.35-fold decrease in IL-1 beta, IL-6 and TBARs after 6 month treatment (p<0.001), respectively. Although, IL-1 and IL-6 revealed a few correlations with classical indices of disease activity no association was found between patient clinical status improvement and cytokine changes over 6 month treatment. CONCLUSIONS: MTX in combination with prednizone decreases blood levels of IL-1 beta and IL-6 and inhibits the intensity of free radical- mediated processes in RA subjects. Monitoring of plasma concentrations of these cytokines could not predict the treatment efficacy. | |
| 9361154 | Pharmacology and pharmacokinetics of methotrexate in rheumatic disease. Practical issues i | 1997 Nov | Methotrexate (MTX) is among the most effective drugs for treatment of rheumatoid arthritis and has been proven valuable in the treatment of multiple other disorders of immune regulation. MTX has been administered at a wide range of doses and dose intervals, in conjunction with multiple other drugs, and in patients with a broad range of concomitant disorders. To design a safe and effective MTX treatment plan for an individual patient, the provider must have knowledge of the pharmacology and drug interactions of this effective but potentially dangerous medication. The first section of the article reviews MTX structure, pharmacology pharmacokinetics, and mechanisms of action in rheumatic disease. The second section examines factors that can be used to increase MTX efficacy and decrease toxicity. | |
| 9669212 | Long-term exposure to methotrexate induces immunophenotypic changes, decreased methotrexat | 1997 Nov | Methotrexate (MTX) treatment of rheumatoid arthritis may require increasing doses to maintain clinical efficacy. An overall plateau of clinical response is reached after only six months of treatment. To study the immunologic, biochemical and genetic effects of MTX on T cells, the Jurkat T cell line was made MTX-resistant by serial addition of methotrexate sodium into culture medium. Cells proliferated and divided successfully in MTX concentrations ranging to 15 microM. MTX resistance of Jurkat T cells in vitro was accompanied by significantly (P < 0.05) decreased expression of CD2, CD3, CD4, CD28, and CD69, IL-2 production, and MTX uptake assessed by cell association or disassociation of 3[H]-MTX or fluoresceinated MTX (FMTX), respectively. In addition, there was DHFR gene amplification and increased levels of DHFR in all resistant cell lines. Both permanent and transient phenotypic changes developed in resultant cell lines exposed to increasing concentrations of MTX in vitro. Expression of CD4 and CD25 and sensitivity to MTX returned to near-parental levels after removal of MTX from culture medium, whereas expression of CD26 and MTX uptake were significantly increased. Expression of CD2, CD3, CD69 and IL-2 production as well as the DHFR levels did not return to the parental phenotype after removal from MTX. We conclude that MTX-cultured cells express depressed levels of cell-surface markers vital for T cell function and activation. The return of enhancement of these cell-surface markers critical to T cell activation suggests a possible mechanism for the severe flares experienced by rheumatoid arthritis patients when drug treatment is discontinued. |