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ID PMID Title PublicationDate abstract
10219258 Suppressive influences of methotrexate on the generation of CD14(+) monocyte-lineage cells 1999 Apr An adequate supply of peripheral blood monocytes, granulocytes, and platelets is necessary for an optimal inflammatory process. We have previously demonstrated that the generation of CD14(+) monocyte lineage cells from the bone marrow is accelerated in patients with rheumatoid arthritis (RA). The current studies examined the influences of methotrexate (MTX), a potent disease modifying antirheumatic drug (DMARD), on the capacity of bone marrow progenitor cells to generate CD14(+) cells in patients with RA, in order to delineate its mechanism of action. CD14(-) cells purified from bone marrow specimens of 14 patients with active RA were cultured in the presence or the absence of pharmacologically attainable concentrations of MTX (0.2 microM). After incubation for 14 days, the cells were analyzed by flow cytometry for expression of CD14 and HLA-DR. The generation of CD14(+) cells from RA bone marrow CD14(-) progenitor cells was significantly suppressed by MTX. However, the expression of HLA-DR on bone marrow-derived CD14(+) cells was not significantly influenced by MTX. There was no significant difference in the effect of MTX on the generation of CD14(+) cells between patients with prednisolone and those without prednisolone. The production of IL-12 in bone marrow cell cultures was not inhibited, but was rather enhanced, by MTX, suggesting that the suppression of the generation of CD14(+) cells might not be due to the inhibition of cytokine production. The results are consistent with the hypothesis that one of the effects of DMARDs may involve the interference with monocyte differentiation in the bone marrow. Moreover, the data suggest that the generation of CD14(+) cells and the expression of HLA-DR on such marrow-derived CD14(+) cells are regulated by different mechanisms.
9278181 In vitro effect of gold sodium thiomalate and methotrexate on tumor necrosis factor produc 1997 Feb We studied the in vitro action of gold sodium thiomalate (GSTM) and Methotrexate (MTX) on spontaneous and lipopolysaccharide (LPS) stimulated TNF alpha production by peripheral blood mononuclear cells (PBMC) of patients with rheumatoid arthritis (RA) and normal healthy individuals. GSTM and MTX (10 microg) each were added to the cultures of PBMC either in medium alone (spontaneous) or in the presence of 10 microg of LPS. GSTM and MTX augmented spontaneous TNF alpha production in normal individuals and patients with RA but did not influence LPS stimulated TNF alpha production. However, TNF alpha production by the PBMC of normal individuals was inhibited if the PBMC were stimulated with LPS, for 6 or 12 h, washed to remove LPS and subsequently incubated with GSTM. These data indicate that GSTM can inhibit TNF alpha production when the PBMC are preactivated by LPS.
10589363 Use of combination therapy in the routine care of patients with rheumatoid arthritis: phys 1999 Nov AIMS: To describe the utilization of combination therapy in the treatment of rheumatoid arthritis (RA). METHODS: Review of published articles and abstracts, and patient/physician questionnaire data. RESULTS: Combination therapy was rarely used in the early 1980s and is now (1999) used for about 25% of RA patients in the US. Physician and patient surveys indicate that methotrexate plus hydroxychloroquine is the most commonly used combination in North America, and physician surveys indicate that methotrexate plus sulfasalazine is the most commonly used combination in Europe. Patient questionnaire data indicate that 13.4% of patients in the US take methotrexate and hydroxychloroquine, and between 11% and 15% of patients with recent onset of RA receive treatment with disease-modifying antirheumatic drug (DMARD) combinations. CONCLUSIONS: Combination therapy with agents such as hydroxychloroquine and methotrexate is used in up to 25% of RA patients in the US, but the use of "aggressive combination therapy" is unusual. Whether combination therapy as currently practiced is beneficial remains to be determined.
9375866 Importance of psychological well being and disease activity in termination of an initial D 1997 Nov OBJECTIVE: To estimate the frequency of and to identify possible risk factors involved with terminating an initial disease modifying antirheumatic drug (DMARD) therapy. We hypothesized that treatment termination depends not only on side effects and inefficacy but also on the therapeutic setting and the health beliefs of the patient. METHODS: We observed an inception cohort of 302 patients with early rheumatoid arthritis (< 2 years) and first prescription of DMARD for 3 years. Survival analysis was used to estimate treatment continuation under rheumatological care. The study group comprised 4 rheumatological outpatient clinics and 7 private practices in Berlin. RESULTS: Of the initial cohort 80% continued the same drug or were in remission after one year, 70% after 2 years. Within the first 2 years, methotrexate therapy was terminated in 15% of the cases and sulfasalazine therapy in 40%, respectively. In both forms of therapy, the discontinuation rate was dependent on initial disease activity. However, the influence of the patient's psychological status at baseline was equally strong. DMARD treatment was terminated earlier and more frequently in patients with poor psychological well being. These findings hold true after controlling for disease activity or severity. CONCLUSION: Patient psychological well being and disease activity at start of initial DMARD therapy are important predictors of early drug discontinuation. By influencing psychological well being (e.g., by patient education programs), continuation of DMARD therapy might be further improved.
9379448 Synthesis and evaluation of novel fluorinated methotrexate derivatives for application to 1997 Sep 26 An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses to both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.
10646485 The role of current strategies in the future treatment of rheumatoid arthritis. 1999 Nov Rheumatoid arthritis (RA) is a serious, chronic, debilitating disease for which no cure is available. Therapeutic aims for patients with RA are to alleviate symptoms, slow disease progression and optimize quality of life. In recent years, measures to achieve these goals have changed, and the development of new drugs will probably result in new treatment regimens. Two drugs with an extensive record of clinical experience are methotrexate and cyclosporin. Methotrexate is widely used because of its efficacy and high therapy retention rate. Both drugs have been shown to slow the progression of RA, but not without side-effects that sometimes preclude their use. As neither drug generally induces remission, improved treatments are needed. Combination therapy using drugs with different mechanisms of action is beginning to be evaluated, as are biological response modifiers targeted to specific mediators of the immune response. The future treatment of RA should provide more effective relief with fewer side-effects.
9517759 Methotrexate and cyclooxygenase metabolism in cultured human rheumatoid synoviocytes. 1998 Mar OBJECTIVE: Our objective was to characterize the effect of methotrexate (MTX) on prostaglandin E2 (PGE2) synthesis in cultured human rheumatoid synovial cells. Prostaglandins (PG) are important mediators of inflammation and joint destruction in rheumatoid arthritis (RA). Two isoforms of cyclooxygenase (COX), the key enzyme in PG synthesis, have been characterized: a constitutively expressed form, COX-1, and an inducible form, COX-2. The mechanisms of action of low dose MTX in RA treatment are still poorly understood. As the clinical effects are often first noticed within a month of starting MTX therapy, an antiinflammatory action has been proposed. METHODS: Adherent synovial cells were obtained by collagenase digestion of rheumatoid synovium, isolated from patients with RA undergoing synovectomy. Between passages 3 and 6, cultured synovial cells were incubated with or without MTX for 54 h, at various concentrations. Interleukin (IL)-1beta (1 ng/ml) was added or not for the last 6 h of incubation. Supernatants were harvested and assayed for PGE2 by enzyme immunoassay (EIA). Exogenous [1-14C]arachidonic acid metabolism of synoviocytes was analyzed by reverse phase high performance liquid chromatography (RP-HPLC). COX-1 and COX-2 mRNA expression was determined by total RNA extraction and reverse transcription polymerase chain reaction. RESULTS: Cellular viability was not affected by MTX. EIA showed that MTX decreased IL-1beta induced PGE2 production by synoviocytes in a dose dependent manner. RP-HPLC analysis confirmed the inhibition of PGE2 and (12S)-12-hydroxy-5,8,10-heptadecatrienoic acid production. COX-1 and IL-1beta induced COX-2 mRNA expression were not inhibited by MTX. CONCLUSION: MTX has an inhibitory effect on IL-1beta stimulated production of PGE2 by cultured human rheumatoid synoviocytes, without affecting either COX mRNA expression. Among various biochemical and immunologic events, MTX could have an antiinflammatory action by decreasing PGE2 release.
10796419 Cyclophosphamide for rheumatoid arthritis. 2000 OBJECTIVES: To estimate the short-term effects of cyclophosphamide for the treatment of rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's Register, the Cochrane Controlled Trials Register, Medline and Embase up to and including July 1997. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. SELECTION CRITERIA: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing oral cyclophosphamide against placebo (or an active drug at a dosage considered to be ineffective) in patients with rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: Data abstraction was carried out independently by two reviewers. The same two reviewers using Jadad's scale (Jadad 1995) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for baseline and end-of-study. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout. MAIN RESULTS: A total of 70 patients were included in the pooled analysis of two trials, 31 receiving cyclophosphamide. A statistically significant benefit was observed for cyclophosphamide when compared to placebo for tender and swollen joint scores: SMDs were -0.57 and -0.59 respectively. The difference in ESR also favoured the active drug but did not reach statistical significance (-12 mm, 95%CI: -26 to 2.5). One trial reported the number of patients developing new or worse erosions: the OR for cyclophosphamide compared to placebo was 0.17 (95% CI: 0.05 to 0.57). Patients receiving placebo were six times more likely to discontinue treatment because of lack of efficacy than patients receiving cyclophosphamide. Withdrawals from adverse reactions were higher in the cyclophosphamide group (Odds ratio=2.9), although this difference was not statistically significant. Side effects from cyclophosphamide included hemorrhagic cystitis, nausea, vomiting, leucopenia, thrombocytopenia, alopecia, amenorrhea and herpes zoster infections. REVIEWER'S CONCLUSIONS: Cyclophosphamide appears to have a clinically and statistically significant benefit on the disease activity of patients with RA, similar to some disease modifying antirheumatic drugs (DMARDs) such as antimalarials or sulfasalazine, but lower than methotrexate. Toxicity however is severe, limiting its use given the low benefit-risk ratio compared to other antirheumatic agents.
10955325 Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treate 2000 Aug OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.
10525317 Flow cytometric detection of type 1 (IL-2, IFN-gamma) and type 2 (IL-4, IL-5) cytokines in 1999 Oct Type 1 cytokines (a.o. IL-2 and IFN-gamma) play an important role in the pathogenesis of rheumatoid arthritis. On the other hand, IgE-mediated diseases such as allergic asthma and atopic dermatitis show a type 2 cytokine (amongst others IL-4 and IL-5) profile. This study examined simultaneously the intracellular production of IL-2, IFN-gamma, IL-4 and IL-5 in T-lymphocytes of patients with rheumatoid arthritis during treatment with methotrexate or salazopyrin, patients with allergic asthma or atopic dermatitis under stable treatment, compared to healthy controls.A three-colour flow cytometric analysis was used for cytokine detection in T-helper cells and T-suppressor/cytotoxic cells. Compared to controls, patients with symptomatic atopic dermatitis showed an increased number of IL-4-producing T-helper lymphocytes in basal circumstances (P=0.001), in contrast to asymptomatic allergic asthma patients. Compared to controls, rheumatoid arthritis patients, treated with salazopyrin, showed an increased number of IL-2-producing T-helper and T-suppressor/cytotoxic lymphocytes after in vitro stimulation with PMA and ionomycin (P=0.01). In contrast, rheumatoid arthritis patients, treated with methotrexate, a more potent disease modifying drug, did not show this type 1 cytokine profile. A positive correlation was found between the number of IFN-gamma producing T-helper cells and disease activity (Ritchie Index and number of swollen joints) in both rheumatoid arthritis patient groups. Active atopic dermatitis patients showed a type 2 cytokine profile, whereas stable asthma patients with lower disease activity did not show a predominance of type 2 cytokines. Rheumatoid arthritis patients under treatment with salazopyrin had a type 1 cytokine profile, which could not be demonstrated in patients treated with methotrexate. This imbalance between type 1 and type 2 cytokines in different immune mediated disorders can be related with treatment and the grade of disease activity. These results stress the need for further investigation of the influence of therapy on cytokine profiles.
11725485 Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases. 2001 Oct The availability of agents that block the biological activity of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis (RA) has permitted studies that confirm the key role of this cytokine in the pathogenesis of this disease. To date, two anti-TNF agents, infliximab and etanercept, have been approved for use in treatment. Clinical trials of these agents demonstrate efficacy for the control of symptoms and signs and acceptable safety in patients who have failed to respond adequately to conventional therapy. Combination with methotrexate appears to be particularly effective and may provide the main initial indication for clinical application in the first instance. Repeated administration of anti-TNF therapies over a one year period results in sustained reduction in symptoms and signs of RA in the majority of patients. It has recently become apparent that anti-TNF therapy protects joints from structural damage. These findings imply that TNF alpha has a critical role in the bone and cartilage damage associated with RA. Evidence to date support the hypothesis that there are 2 particularly important mechanisms of action; deactivation of the proinflammatory cytokine cascade at the site of inflammation and diminished recruitment of inflammatory cells from blood to the rheumatoid joint.
11333345 Combination therapy in rheumatoid arthritis. 2001 May It has become clear that early suppression of rheumatoid arthritis disease activity is important in preventing progressive joint destruction and functional decline. To achieve this goal, many rheumatologists today advocate a more aggressive approach, using combinations of classic disease-modifying antirheumatic drugs-often including methotrexate-or new drugs. During the last 2 years, the combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone has been demonstrated to be more beneficial than monotherapy in patients with early rheumatoid arthritis. In addition, the superior efficacy of the combination of new tumor necrosis factor-alpha blocking agents plus methotrexate to methotrexate alone in patients with chronic disease is very promising. Most studies of combination therapy focus on the efficacy of a combination compared with monotherapy, rather than on the efficacy of a treatment strategy. Although these studies of combination therapy provide useful information about the possible synergistic action of combinations of drugs, many questions remain unanswered, and studies evaluating different treatment strategies are needed before a new approach can be suggested.
10432311 Methotrexate inhibits the first committed step of purine biosynthesis in mitogen-stimulate 1999 Aug 15 The immunosuppressive and anti-inflammatory effects of low-dose methotrexate (MTX) have been related directly to inhibition of folate-dependent enzymes by polyglutamated derivatives, or indirectly to adenosine release and/or apoptosis and clonal deletion of activated peripheral blood lymphocytes in S-phase. In this study of phytohaemagglutinin-stimulated primary human T-lymphocytes we show that MTX (20 nM to 20 microM) was cytostatic not cytotoxic, halting proliferation at G(1). This stasis of blastogenesis was associated with an inhibition of purine ribonucleotide synthesis but a stimulation of pyrimidine biosynthesis, the normal mitogen-induced expansion of ATP and GTP pools over 72 h being restricted to concentrations of unstimulated T-cells, whereas the increment in UTP pools exceeded that of controls. Decreased incorporation of H(14)CO(3) or [(14)C]glycine into purine ribonucleotides, with no radiolabel accumulation in any de novo synthetic intermediate but enhanced H(14)CO(3) incorporation into UTP, supported these MTX-related effects. Exaggerated [(14)C]hypoxanthine salvage (which normalized the purine and UTP pools) confirmed the increased availability of 5-phosphoribosyl-1-pyrophosphate (PP-ribose-P) as the molecular mechanism underlying these disparate changes. These results provide the first substantive evidence that the immunosuppressive effects of low-dose MTX in primary blasting human T-lymphocytes relate not to the inhibition of the two folate-dependent enzymes of purine biosynthesis but to inhibition of the first enzyme, amidophosphoribosyltransferase, thereby elevating PP-ribose-P and stimulating UTP synthesis. Varying cell types or incubation conditions employed by other workers, especially malignant/activated cells with high basal metabolic rates, might mask the effects noted in primary human T-lymphocytes. The findings imply the involvement of low-dose MTX in the inhibition of T-lymphocyte proliferation and proliferation-dependent processes in rheumatoid arthritis.
10589359 Combination DMARD therapy including corticosteroids in early rheumatoid arthritis. 1999 Nov A number of reports indicating the growing acceptance of simultaneous therapy with multiple disease-modifying anti-rheumatic drugs (DMARDs), as well as the use of more aggressive treatment measures in the early phases of disease to combat rheumatoid arthritis (RA), have appeared during the last decade. However, only a few randomized controlled clinical trials have been conducted on the use of DMARD combinations in early RA. We review these trials in this article. In two separate one-year studies combination therapy with sulphasalazine (SSZ) and methotrexate (MTX) seemed to offer no benefits compared to either drug used as monotherapy. On the other hand, the DMARD combinations so far proven to be superior to single DMARDs have initially also included a corticosteroid component. In the COBRA study (Combinatietherapie Bij Reumatoide Artritis) the combination of SSZ (2 gm/day), MTX (7.5 mg/week for 40 weeks), and prednisolone (Prd) (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day and stopped after 28 weeks) compared to SSZ alone (2 gm/day) resulted in significantly better clinical outcomes at week 28. Although the difference in clinical response between the treatment arms was lost at week 58, the progression of joint damage remained statistically significantly slower at week 80 in the patients initially assigned to the combination therapy. Furthermore, in the FIN-RACo trial (Finnish Rheumatoid Arthritis Combination Therapy Trial), therapy using a "tailored-steps" strategy with SSZ (1-2 gm/day), MTX (7.5-1.5 mg/week), hydroxychloroquine (300 mg/day), and Prd (up to 10 mg/day) yielded a significantly increased remission rate and less peripheral joint damage at two years than the single DMARD treatment strategy (initially SSZ 2 gm/day), with or without Prd. Adverse effects in both study arms were comparable. Two additional preliminary reports (in abstract form) suggest that intensive local therapy in the form of intra-articular injections added to single or combination therapy improves both local and systemic disease control, with increased remissions and less damage. Although still preliminary, these results should encourage the rheumatological community to treat selected RA patients with DMARD combinations from the very start.
11312373 Amelioration of rat antigen-induced arthritis by liposomally conjugated methotrexate is ac 2001 Apr OBJECTIVES: We examined the temporal changes in the expression of interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the rat antigen-induced arthritis (AIA) model and investigated how their expression was modulated following disease amelioration by liposomally conjugated methotrexate (G-MLV). METHODS: On the day of arthritis induction (day 0), rats were treated with a single intra-articular injection of G-MLV, methotrexate (MTX), a dose of lipid equivalent to G-MLV (E-LIPO) or saline. On days 3 and 7 after disease induction, animals from each experimental group were killed. Joint tissue was examined histologically and for mRNA expression (IL-6, IL-1beta and TNF-alpha) using semiquantitative reverse transcription-polymerase chain reaction. RESULTS: There was no significant difference (ANOVA) in knee swelling between MTX-, E-MLV- or saline-treated animals from day 0 to day 7. By day 1, G-MLV significantly reduced knee swelling (1.94+/-0.12 mm; P<0.0001) compared with rats treated with MTX (3.17+/-0.18 mm). G-MLV treatment also significantly inhibited the histological progression of AIA. This reduction in disease severity was accompanied by a reduction in IL-1beta mRNA expression in synovial tissue extracts on day 3 and IL-6 mRNA expression on both day 3 and day 7. CONCLUSIONS: Liposomally conjugated MTX may exert its beneficial effects in experimental arthritis through IL-1beta and IL-6 inhibition.
11543695 Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis. 2001 There is increasing interest in using combinations of two or more disease modifying anti-rheumatic drugs to treat rheumatoid arthritis. The use of such combinations is increasing in routine clinical practice. We have identified 18 well-conducted, randomised controlled trials of the use of combinations of disease modifying drugs, and a number of open studies that provide helpful supportive information. The 18 trials involved 2221 patients. Two trials reported strongly positive results, six reported moderately positive results and ten gave largely negative results. The combination of methotrexate, sulfasalazine and hydroxychloroquine appears to be effective with an acceptable level of adverse effects. There is also evidence that the combination of methotrexate and cyclosporin is advantageous. With both combinations, there appears to be further advantages from using corticosteroids in addition to the combination, although the evidence for this is incomplete. The use of other combinations is of less value, and in particular combinations involving parenteral gold, penicillamine and azathioprine are best avoided. Finally, there is growing evidence from randomised trials that the combination of anti-tumour necrosis factor (TNF) therapy with methotrexate is effective and well tolerated. We have identified four randomised controlled trials of the use of combinations of anti-TNF with methotrexate that all reported results favouring this combination. There is insufficient evidence to support the use of other combinations involving immunotherapies at the present time.
9599798 Lymphoma with regression after methotrexate withdrawal in a patient with rheumatoid arthri 1998 Apr We report a new case of large T-cell lymphoma in a rheumatoid arthritis patient under low-dose methotrexate (cumulative dose: 750 mg). Serologic tests for the Epstein-Barr virus were positive, and the viral RNA was demonstrated in the lymphoma cells. As in a few other cases reported in the literature, the clinical and laboratory test abnormalities resolved promptly after methotrexate withdrawal without anticancer therapy. The patient was still in complete remission at last follow-up four years later.
9336418 Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associate 1997 Oct 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.
11548909 A clinical and economic review of disease-modifying antirheumatic drugs. 2001 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.
9117176 N-acetyl-beta-D-glucosaminidase urinary excretion as an early indicator of kidney dysfunct 1997 Jan The N-acetyl-beta-D-glucosaminidase (NAG) activities and albumin levels in the urine of 32 patients with active rheumatoid arthritis treated with low-dose pulse methotrexate (MTX) have been investigated. An increase in NAG urinary excretion was more frequent than the incidence of micro- or macroalbuminuria on entry, and during treatment with MTX. There was also a significant decrease in NAG levels observed at week 24. Parameters such as patient's age, time from onset, previous and current treatment did not allow us to predict the degree of NAG enzymuria. We conclude that MTX does not cause marked damage to renal proximal tubules; on the contrary, the observed significant decrease of urinary NAG on week 24 could be interpreted as a beneficial effect of MTX on kidney function. Early detection of high NAG enzymuria and elevated albumin levels in urine before the initiation of MTX therapy could be helpful in predicting possible MTX toxicity probably related to impaired renal clearance of MTX. Patients withdrawn from the study for non-renal-related adverse events also had an unusually large increase in urine NAG activity and urine albumin levels.
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