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ID PMID Title PublicationDate abstract
11709606 Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated 2001 Nov OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).
9189054 Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an ope 1997 May A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.
11352236 American College of Rheumatology criteria for improvement in rheumatoid arthritis should o 2001 May OBJECTIVE: Change in a patient's condition is expressed as a percentage of the baseline value for a core set of measures in the American College of Rheumatology (ACR) improvement criteria for rheumatoid arthritis (RA), and this is used as the basis to decide whether a patient has improved. The result is dependent on whether the underlying measure has a score that increases or decreases on improvement. We examined the importance of this effect in the application of the ACR improvement criteria. METHODS: Data were obtained from the COBRA trial, in which 155 patients with early active RA had been randomized to receive either combination treatment with step-down prednisolone, methotrexate, and sulfasalazine or sulfasalazine alone. Patient and physician global assessments were recoded to reflect decreasing scores on improvement. The effects of this difference in scoring systems were compared among 3 response criteria levels (20%, 50%, and 70%) that are currently being used to assess improvement in RA clinical trials. RESULTS: Analyses showed that the effects of a decreasing, versus increasing, score on the designation of improvement cannot be ignored, especially at higher percentages of improvement (e.g., 50%, 70%). CONCLUSION: We recommend that percentage improvement in RA be calculated only on scores that decrease on improvement. When necessary, raw data should be recoded before the ACR improvement criteria are applied.
9676755 Is there an optimal time to administer methotrexate in the treatment of rheumatoid arthrit 1998 Jul OBJECTIVE: To determine the optimal time to administer methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: In a crossover study 23 patients were administered MTX intramuscularly at either 10 AM or 6 PM. A 2 week interval separated the 2 injections. MTX concentrations were measured using a fluorescence polarization immunoassay. Pharmacokinetic variables were estimated using a Bayesian approach. The morning and evening schedules were compared using analysis of variance to determine the optimal time of injection. RESULTS: No statistical difference was found in the pharmacokinetics of MTX according to hour of injection. A difference in the creatinine clearance, however, was observed in the samples obtained at noon and 8 PM, but clearance of MTX was unchanged. CONCLUSION: Pharmacokinetic variables suggest that MTX can be administered either in the morning (10 AM) or evening (6 PM) in the treatment of RA.
9204252 Disease-modifying antirheumatic drugs. 1997 May The case for early intervention with disease-modifying antirheumatic drugs is strengthened by published reports during the past year. These drugs include methotrexate, gold sulfasalazine, and antimalarial agents. The American College of Rheumatology issued guidelines for the management of rheumatoid arthritis and for monitoring the toxicity of antirheumatic drugs. Studies on the mechanisms of action of disease-modifying antirheumatic drugs focused on their effects on cytokines and their receptors. The toxic effects of disease-modifying antirheumatic drugs remained an important issue, especially the adverse pulmonary effects of methotrexate. An important trial demonstrated a beneficial effect of triple disease-modifying antirheumatic drug therapy (methotrexate, sulfasalazine, and hydroxychloroquine) over individual agents.
10895374 Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with ch 2000 May OBJECTIVE: To examine the safety of the use of disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with chronic viral hepatitis (CVH). METHODS: Records of 600 Chinese patients satisfying the ARA criteria for RA in two rheumatology centers were reviewed. Patients with CVH were studied. Liver enzymes were checked before (baseline) and during DMARD use at 3-month intervals or more frequently if necessary. Drug-episodes (D-Ep), defined as the continuous use of DMARD, singly or in combination, for more than 6 months in a patient, were analysed. Changes in serum liver alanine transaminase (ALT) levels as multiples of the upper range of normal were taken to reflect the severity of hepatotoxicity. Changes of ALT to > or = 1.5 times the upper range of normal if they were measured at baseline or > or = 2 times the upper range of normal if they were measured during and after the use of DMARD were considered as abnormal. Control patients included those with CVH alone (n = 623) or RA without CVH (n = 62) matched for age, sex and D-Ep. RESULTS: 30 RA patients were found to have concomitant CVH. One patient was excluded because of use of NSAID alone (n = 1). Among the 29 patients, 23 were HBsAg +ve and 6 were anti-HCV Ab +ve. A total of 47 D-Ep were analysed. 20/47 (42.6%) of D-Ep in 16/29 (55.2%) RA + CVH patients developed abnormal ALT levels after a mean 1.9-year duration of DMARD use. This was statistically significant when compared with 13/94 (13.8%) of D-Ep which ended with abnormal ALT levels in 13/62 (21%) patients with RA alone (p < 0.0001 for D-Ep which ended up with abnormal ALT, and p < 0.02 for the number of patients who developed abnormal ALT) and 128/623 (20.5%) patients with CVH alone (p < 0.005). 53% (9/17) of hydroxychloroquine (HCQ) D-Ep were associated with an abnormal outcome. Corresponding figures for sulphasalazine (SAZP) and oral or intramuscular gold preparations were 55.6% (5/9) and 0% (0/3) respectively. Two patients on methotrexate, used either singly or in combination, had normal ALT levels throughout the study period. One patient on azathioprine developed reactivation of hepatitis B infection. When D-Ep of the RA + CVH group were further analysed, 16/43 (37.2%) and 4/4 (100%) D-Ep which started with normal and abnormal baseline ALT respectively developed further liver enzyme derangement. CONCLUSION: The use of DMARD in RA + CVH patients is associated with a high incidence of hepatotoxicity. The effect is likely to be synergistic. This includes drugs such as HCQ, which is generally believed to be less hepatotoxic.
10943872 Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunom 2000 Aug OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue. METHODS: In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1). RESULTS: Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.
10889331 New gamma-fluoromethotrexates modified in the pteridine ring: synthesis and in vitro immun 2000 May Our continuing program to develop new antifolate drugs useful against rheumatoid arthritis led us to modify the pteridine ring of gamma-fluoromethotrexate. Pyrrolopyrimidine derivatives 1e and 1t were found to exhibit potent suppressive effects on the responses of both T and B cells to mitogens, although tetrahydropyridopyrimidine derivatives 2e and 2t and quinazoline derivatives 3e, 3t and 4e showed very weak suppressive activities. Thus, conversion of the pteridine ring of gamma-fluoromethotrexate to a pyrrolopyrimidine ring led to a new potential antirheumatic compound.
9572644 Perforation of the sigmoid colon in a rheumatoid arthritis patient treated with methylpred 1998 We describe a 61 year-old caucasian male diagnosed with rheumatoid arthritis. He was started on methylprednisolone pulses because of a severe flare of symmetric polyarthritis while he was on weekly intramuscular methotrexate and low-dose oral prednisone. After the second pulse of methylprednisolone the patient suddenly developed severe abdominal pain with free air under the right hemidiaphragm in the chest roentgenogram. The emergency surgery revealed the perforation of a colonic diverticulum. We suggest that methylprednisolone pulses should be carefully used in those patients over 50 years of age and/or people with demonstrated or suspected diverticular disease.
10074595 Remission of the nephrotic syndrome in a patient with renal amyloidosis due to rheumatoid 1998 Nov A 46-year-old woman developed nephrotic syndrome secondary to rheumatoid arthritis (RA). A renal biopsy showed deposition of amyloid fibrils in the subendothelial space of the glomerular capillary walls. After treatment with prednisolone (PSL, 40 mg/day), the levels of C-reactive protein (CRP) and serum amyloid A decreased to within normal limits for 2 weeks. However, the nephrotic syndrome persisted for 6 months after the therapy. To maintain the suppression of disease activity and to reduce PSL, methotrexate (5 mg/week) was added. The nephrotic syndrome resolved gradually, and the level of serum albumin returned to normal. Although renal prognosis of patients with nephrotic syndrome due to amyloidosis caused by RA has been considered poor, adequate and long-term treatment of RA with antiinflammatory drugs, including PSL and methotrexate, is useful for patients with secondary amyloidosis complicated by RA.
11249572 TNF inhibitors in the treatment of arthritis. 2000 Oct Rheumatoid arthritis (RA) is a chronic destructive arthritis leading to joint destruction as a consequence of chronic inflammatory processes. Established therapy with slow-acting disease-modifying anti-rheumatic drugs (DMARDs), as with low-dose methotrexate (MTX), leads to a significant improvement of disease symptoms, but are unable to stop joint destruction. Novel therapeutic agents like monoclonal antibodies (mAb), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA and in other chronic arthritides like ankylosing spondylitis or psoriatic arthritis with convincing success. In particular, clinical trials testing anti-TNF alpha agents either alone or in combination with MTX have proven the feasibility and efficacy of these novel approaches.
10745935 [Role of anti-TNF therapy in rheumatoid arthritis]. 2000 Mar 11 TUMOR NECROSIS FACTOR: TNF is a cytokine produced by several types of cells, but mainly by monocyte-macrophages, activated endothelial cells, fibroblasts, and joint cartilage chondrocytes. The circulating form of TNF alpha (homotrimere) is derived from its membrane form by cleavage induced by a metalloprotease called TACE. This cytokine plays a pivotal role in the inflammatory reaction in conjunction with IL-1 and IL-6. The effect of TNF alpha is mediated by two membrane receptors carried on the surface of target cells (TNF-RI p55 and TNF-RII p75) which are released into the biological fluids (synovial fluid and plasma). ARGUMENTS FOR A PATHOGENIC ROLE: Transgenic mice carrying the human gene for TNF alpha develop polyarthritis suggesting this cytokine is directly implicated in the pathogenesis. In diverse cell types in rheumatoid joints, TNF alpha and its receptors can be identified by immunohistochemistry techniques as can TNF alpha mRNA by RT-PCR. THERAPEUTIC POSSIBILITIES: Anti-TNF alpha antibodies can effectively attenuate or prevent arthritis in the main experimental models. TNF alpha can also be neutralized with soluble receptors, TNF alpha RI or TNF alpha RII. The efficacy of these two therapeutics has been proven in rheumatoid arthritis, but with a short-term though remnant effect, leading to iterative injections and/or combinations with methotrexate. Short-term side effects are mild but the long-term infectious and oncogenic adverse effects remain to be determined. Is this simply a powerful antiinflammatory treatment or a real curative treatment? A precise examination of radiographic scores will be required to provide the answer to this question.
11036825 Cyclosporin A inhibits CD69 expression induced on synovial fluid and peripheral blood lymp 2000 Oct OBJECTIVE: To study the modulation of CD69 expression on peripheral blood (PB) and synovial fluid (SF) lymphocytes by interleukin 15 (IL-15) and several other cytokines and chemokines widely detected in the rheumatoid microenvironment. The effect of cyclosporin A (CSA) or methotrexate (MTX) in the cytokine mediated regulation of CD69 was analyzed. METHODS: CD69 expression on lymphocytes was assessed by flow cytometry after incubation with different cytokines, chemokines, phorbol myristate acetate, or calcium ionophore in the presence or absence of CSA, MTX, or both. The effect of IL-15 and SF supernatants in maintaining CD69 expression on SF lymphocytes was also assessed. IL-15 levels in SF supernatants were measured by ELISA. RESULTS: IL-15 induced the greatest upregulation of CD69 expression on PB lymphocytes in a time and dose dependent manner. IL-15 was able to maintain a high CD69 expression on SF lymphocytes. SF supernatants from rheumatoid arthritis (RA), which contain significant amounts of IL-15, also reversed the CD69 downregulation of SF lymphocytes in culture. CSA, but not MTX, inhibited the CD69 upregulation mediated by IL-15 both in PB and SF lymphocytes. CONCLUSION: IL-15 appears to be responsible, at least in part, for the high CD69 expression on lymphocytes from the rheumatoid microenvironment. Consistent with the virtual absence of lymphocyte derived cytokines in RA synovium, the prevention of IL-15 mediated CD69 upregulation on lymphocytes may explain the effect of CSA in the treatment of RA.
10589365 Clinical experience with combination disease-modifying antirheumatic drug therapy with cyc 1999 Nov OBJECTIVES: We previously reported on the clinical use of cyclosporine (Neoral), alone or in combination with methotrexate (MTX), in the first 46 refractory rheumatoid arthritis (RA) patients treated at our centre between March 1996 and November 1997. Thirty of the 46 patients remained on cyclosporine at study completion (mean dose 2.98 mg/kg/day) with efficacy inferred by significant reductions in the prednisolone and MTX doses and creatinine maintained in an acceptable range. Early discontinuation was primarily related to non-serious side effects. METHODS: The 30 patients continuing cyclosporine were reviewed 12 months later in November 1998. Analysis included life-table techniques. RESULTS: 21 of the original 46 patients (46%) continued at a mean dose of 2.59 mg/kg/day after a mean of 23.4 months. Nine patients discontinued cyclosporine during this 12-month period: 3 due to inactive disease, 2 due to hypertension, 2 due to elevated creatinine, and 1 due to mononeuritis multiplex secondary to rheumatoid vasculitis, and 1 due to inefficacy. Patients continuing cyclosporine had a shorter disease duration (9.85 versus 15.5 years [P = 0.05]). The prednisolone dose decreased from a baseline value of 10.57 mg/day to 6.78 mg/day (P = 0.007) and the MTX dose from 15.6 mg/week to 13.1 mg/week (P = 0.02). The mean serum creatinine level increased from a baseline of 73.86 mumol/l to 85.8 mumol/l (16%). 21/30 patients on combination therapy with MTX showed no difference in discontinuation rates compared with those on cyclosporine alone. Life-table analysis showed a bimodal distribution with significantly increased cyclosporine discontinuation in the first 12 months (principally due to non-renal/hypertensive causes) versus the subsequent period. CONCLUSION: This follow-up study indicates that the use of cyclosporine in refractory RA allows a reduction in the prednisolone and MTX doses. Utilization is longer in earlier disease and is unaffected by combination with MTX. Renal function is maintained within an acceptable range. The bimodal discontinuation curve reflects early patient/physician concern about minor side effects, while renal/hypertension changes resulted in later discontinuation.
9330929 Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis 1997 Oct OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.
12575588 [Clinical observation on small doses Tripterygium wilfordii polyglycoside combined with me 2001 Dec OBJECTIVE: To observe the effect and adverse reaction of small doses Tripterygium wilfordii polyglycoside (TWP) combined with methotrexate (MT) in treating rheumatoid arthritis (RA). METHODS: Seventy RA patients were randomly divided into two groups, the control group (35 patients) and the TWP combined MT Group (TWPM group). Both of them were continued to use the non-steroidal anti-inflammatory drugs. The control group took MT 15 mg orally, once every week; the TWPM group took TWP 10 mg orally, 3 times a day, and MT 7.5 mg orally once every week. The clinical effect and adverse reaction after treatment were evaluated. RESULTS: The markedly effective rate in the control group and the TWPM group was 28.6% and 34.3% respectively, with no significant difference (P > 0.05). Data of symptoms and signs, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) were determined respectively with significant difference (P < 0.01). The rate of adverse reaction was 20 cases-times in the control group and 8 cases-times in the TWPM group. CONCLUSION: MT combined small doses of TWP in treating RA has better effect and less adverse reactions than un-combined MT.
9312762 [The effect of immunosuppressive drugs on expression of surface antigens of lymphocytes in 1997 Feb One hundred and fifty patients with rheumatoid arthritis (RA) were treated with immunosuppressive drugs for 12 months. Fifty nine patients were treated with methotrexate (MTX), 15 with cyclophosphamide (CTX), 30 with prednisone (PRE) and 46 with non steroidal antiinflammatory drugs (NSAID). The cell surface phenotype of lymphocyte was analyzed using immunofluorescence methods ans a variety of monoclonal antibodies. The studies were performed using fluorescence activated cell scanner (FACScan) and epifluorescence microscope. No changes in the percentage of CD3, CD4, CD8 were observed. However, in the MTX treated group the percentage of CD19+ (15.1% before treatment vs 10.2% after 12 months MTX treatment (p < 0.05) and CD5+CD19+ B-cells was decreased. In CTX treated group the percentage of both B cells (17.4% vs 11.0% (p < 0.5)) and activated T cells was decreased (CD25+: 2.8% vs 1.1%, p < 0.05 and HLA-DR+: 22.1% vs 12.7%, p < 0.01). Patients treated with prednisone expressed several changes in lymphocyte phenotype i.e. decreasing of activated T cells (CD3+CD25+: 6.9% vs 3.6%, p < 0.01), B cells (CD5+CD19+: 3.4% vs 0.8%, p < 0.001), and NK cells (CD16+: 14.8% vs 8.5, p < 0.01 and CD56+: 16.3% vs 10.7%, p < 0.01). Analyzing immunosuppressive drugs appeared to be very sufficient in the RA treatment. Moreover, the correlation between percentage of both B lymphocytes and activated T cells, and activity of disease were shown.
10420896 [Psoriasis. Rheumatologic manifestations]. 1999 Jun 26 THE CONTEXT: Psoriasic arthritis lies somewhere between rhumatoid polyarthritis and spondyloathropathy. Its prevalence is about 0.1% with a 1/1 sex ratio. Mean age at onset of symptoms is 40 years. In 10 to 15% of the cases, rhumatological manifestations are observed before skin lesions. Ungueal involvement is particularly frequent. FIVE CLINICAL FORMS: Classically, five clinical forms are described: arthritis limited to the distal interphalangeal joints, mutilating arthritis, symmetrical polyarthritis, asymmetrical mono- or oligoarthritis, and spondylitis. Asymmetrical oligoarticular forms and polyarithrtis predominate. DISEASE SEVERITY: In general psoriasic arthritis is a benign condition. Severe forms have however been described with erosion and osteolysis involving the distal interphalangeal joints. Typical radiological may be observed. THERAPEUTIC OPTIONS: Non-steroidal antiinflammatory drugs help control disease progression in about one-third of the cases. In other patients, gold salts, D-penicillamine, methotrexate, or sulfasalazine may be required.
10524688 Comparison of two schedules for administering oral low-dose methotrexate (weekly versus ev 1999 Oct OBJECTIVE: To compare the efficacy of 2 low-dose oral methotrexate (MTX) schedules in maintaining remission in patients with rheumatoid arthritis (RA). METHODS: Patients with RA were included if they were receiving treatment with weekly MTX for at least 9 months and the RA was in remission (defined by American College of Rheumatology [ACR] criteria) for at least 6 months. Patients were stratified by treatment and randomly assigned to weekly or every-other-weekly (EOW; reducing their monthly dose by half) treatment with MTX. Patients were evaluated by a rheumatologist (blinded to the treatment schedule) at baseline and at 6, 12, and 24 weeks. The evaluations included joint counts, Ritchie Articular Index, Health Assessment Questionnaire Disability Index, physician's and patient's global health assessments, visual analog scale for pain, and incidence of adverse effects. Laboratory evaluations were done at baseline and at week 24. RESULTS: Fifty-one patients were included (26 taking weekly MTX, 25 taking EOW MTX). Baseline comparisons showed no differences between the groups. The mean duration of RA was <3 years in both groups, and they had been started on weekly MTX treatment early after diagnosis. After 24 weeks, >90% of the patients in both groups continued in remission. Evaluations of disease activity at 6 and 12 weeks showed no between-group differences. EOW MTX patients who experienced relapse were switched back to weekly MTX, and after a few weeks, their RA was again controlled. The incidence of adverse effects was slightly higher in the weekly MTX group, although the difference did not reach statistical significance. The observed laboratory values were very similar for both groups, except for the serum aspartate aminotransferase and alanine aminotransferase levels, which decreased in the EOW MTX group and were statistically significant at week 24 (P = 0.04 and P = 0.006, respectively). CONCLUSION: EOW MTX represents a valid therapeutic alternative for a specific subgroup of RA patients, as outlined by the ACR remission criteria. Patients with a short disease duration who were treated early after disease onset with weekly MTX and who achieve sustained remission have a higher probability of success with the EOW MTX schedule.
10990220 Folic acid alters methotrexate availability in patients with rheumatoid arthritis. 2000 Sep OBJECTIVE: To evaluate the effects of repeated doses of folic acid on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: We studied 20 patients (ages 30-78 years) who received MTX intramuscularly (10 mm/week). MTX was administered alone or after treatment with folic acid (5 mg tablet once daily) for 13 days. Plasma samples were collected 2 and 8 h after dose intake. MTX concentrations in plasma and ultrafiltrate samples were measured by fluorescence polarization immunoassay. A Bayesian approach was used to determine individual MTX pharmacokinetic variables to minimize the number of samples collected. RESULTS: Folic acid supplementation led to reduced plasma MTX levels 2 and 8 h after MTX administration and reduced area under the plasma MTX concentration versus time curve (AUC) (about 20%; p < 0.02). Total clearance of MTX and Vd were higher when patients were also receiving folic acid than when they were taking MTX alone (p < 0.02). The plasma protein binding of MTX remains unchanged. CONCLUSION: The lower plasma MTX concentrations in patients taking folic acid supplements could be interpreted as increased cellular uptake of MTX; the folic acid supplements would promote the sequestering of MTX intracellularly. The decrease of MTX concentrations leads to reduced AUC; it is also possible that there are reduced AUC combined with increased intracellular folate levels. These results reopen the question of whether folic acid should be used immediately in all patients when MTX is begun.
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