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PMID	Title	PublicationDate	abstract
7612407	Disease-modifying antirheumatic drugs, including methotrexate, gold, antimalarials, and D-	1995 May	Recent literature continues to promote the early use of disease-modifying antirheumatic drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of combination DMARD treatments have been disappointing, and careful attention must be paid to clinical trial design if the efficacy of combination therapies is to be established. Methotrexate retains its prominent role, and its mechanism of action has been the subject of many reports; its toxicity remains the most common reason for treatment termination. Guidelines for monitoring hepatic toxicity of methotrexate have been published and may help reduce the need for invasive biopsy procedures. Significant risk factors for methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled studies of both sulfasalazine and hydroxychloroquine have been reported and have demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis. Awareness of drug-toxicity profiles is important for physicians who prescribe these agents.
8247309	[Weekly low-dose methotrexate in rheumatoid arthritis. Review of the literature].	1993 Oct	Methotrexate (MTX) is an antifolic drug that in recent years has been largely employed in the treatment of Rheumatoid Arthritis (RA). Both short and long term clinical trials have demonstrated its efficacy and good tolerability. It induces a significant improvement of all clinical variables and a decrease in the erythrocyte sedimentation rate and other acute phase reactants with a steroid sparing effect. The probability of continuing MTX therapy for up to 5 years is 46-55% whereas that of continuing gold, hydroxychloroquine, sulfasalazine or D-penicillamine therapy is less than 20%. MTX is a rapidly acting drug with a clinical response within 4 weeks and a plateau phase after 6 months of therapy. Discontinuation of long-term MTX therapy induces a flare-up of the disease so that patients receiving long-term MTX must continue the drug to maintain clinical benefits. In spite of its clinical efficacy, MTX does not seem to have a significant effect on disease progression as determined radiographically. In this respect, MTX appears to have some superiority when compared to azathioprine, but not when compared to gold salts. MTX has been employed in patients with RA unresponsive to other Disease-Modifying Antirheumatic Drugs (DMARDs), but according to some recent views on the therapeutic strategy of RA, it could be used in early RA as a first choice drug. Toxic effects are the main reason in limiting long-term MTX treatment. Hepatic toxicity is one of the more common side-effects of MTX, but the recognition of its "risk factors" such as alcohol abuse, may reduce it. Acute pneumonitis is one of the more severe complications of MTX therapy and may be life-threatening. In RA patients treated with MTX are also reported complications of immunosuppression, such as Pneumocystis carinii pneumonia whose clinical-radiological picture may be similar to that of acute pneumonitis. The mechanism of action of low-dose weekly MTX in RA is still unclear, but it might be more antiinflammatory than immunosuppressive, as supported by the rapid clinical response. The inhibition of Interleukin-1 activity or other inflammatory cytokines and inflammatory cells may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action and its place in the therapeutic strategy of this disease.
8779788	[Untoward effects of low dose methotrexate therapy in rheumatoid arthritis].	1996 Jun	Sixty patients with rheumatoid arthritis who were administered weekly low dose methotrexate (MTX) were retrospectively analyzed for their untoward effects of MTX by interviewing to the patients and by the medical records. Cough and sputa were the most frequent symptoms (23.3%) and gastrointestinal symptoms were the next (20%). Five of 60 patients (8.2%) showed liver function test abnormalities, and four (6.7%) exhibited transient exacerbation of arthralgia for several hours to a few days after MTX administration. Three patients (5%) suffered from interstitial pneumonitis. Hair loss was seen in 3 patients (5%), and headache, leucocytepenia, fever, skin eruption, abnormal taste, hemorrhagic cystitis, and flashing were experienced in a patient, respectively. Three (5%) suffered from fungal infection, and herpes zoster, sepsis, and osteomyelitis were experienced in each one patient, respectively. MTX was withdrawn in three patients (5%) because of cough and sputa the drug was withdrawn in other three patients because of the interstitial pneumonia, and was drawn in another three patients because of transient exacerbation of arthralgia. The drug was withdrawn in each one patient, because of nausea and vomiting, skin eruption, osteomyelitis, and sepsis, respectively. Overall, MTX were withdrawn in 21 patients (35%), and, of those, 13 patients (21.7%) because of untoward effects and 8 patients (13.3%) because of the lack of efficacy.
8230008	Aspirin is not associated with more toxicity than other nonsteroidal antiinflammatory drug	1993 Aug	OBJECTIVE: To compare the clinical and laboratory toxicities of aspirin vs nonsteroidal antiinflammatory drugs (NSAID) in combination with low dose methotrexate (MTX). METHODS: We retrospectively examined 34 patients with rheumatoid arthritis (RA) who completed 12 months of a prospective MTX trial. Analysis included descriptive and logistic regression. RESULTS: Twelve patients took an average of 4.5 g aspirin daily; 22 patients took other NSAID at stable doses. Limiting toxicity was not different between aspirin and NSAID treatment groups, respectively, for stomatitis (33 vs 27%), gastrointestinal symptoms (25 vs 18%), hepatic (25 vs 27%), or other toxicity. However, using logistic regression procedures, weight adjusted weekly MTX dose and prednisone dose correlated with toxicity. CONCLUSION: While toxicity is common when aspirin or NSAID are used with MTX to treat RA, there is no clinical difference between aspirin and NSAID with respect to that toxicity during 12 months of therapy.
8996467	Methotrexate update.	1996	Methotrexate (MTX) has become one of the most widely prescribed second-line agents world-wide for rheumatoid arthritis (RA). Studies have established efficacy in populations which have failed other second-line agents. Although MTX must be considered as a potential hepatotoxin, studies have shown that liver histologic changes can be predicted by monitoring of serum albumin and AST at four to eight week intervals. MTX pulmonary toxicity appears to be more common than liver disease. It most often presents with a subacute course with dry cough and dyspnea with or without fever. Clinicians must be aware of this presentation and withhold the drug when these symptoms appear. MTX may also cause mild renal impairment when used with NSAIDs. This effect has been observed with higher mean weekly doses in the 15 to 20 mg range, but not with a starting dose of 7.5 mg. Although MTX may exhibit a variety of effects in in vitro systems its mechanism of action in patients with RA has not yet been determined.
1629819	Clinical liver disease in patients with rheumatoid arthritis taking methotrexate.	1992 Feb	Between 1981 and 1989, 3 of 134 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) developed clinically significant hepatic dysfunction and showed histologic evidence of severe liver disease (fibrosis and cirrhosis). Factors identified in these patients that may have been linked to liver toxicity included diabetes, congestive heart failure and Felty's syndrome. In the patient group that received a post-MTX liver biopsy, pulmonary fibrosis and obesity were significantly associated with hepatic fibrosis/cirrhosis. Severe liver disease may occur in patients with RA treated with low dose MTX (less than 3%). Early liver biopsy is recommended in selected cases.
7510810	Choroidal infiltrates as the initial manifestation of lymphoma in rheumatoid arthritis aft	1994 Mar	OBJECTIVE: To report the third known and documented occurrence of malignant disease as a complication of immunosuppression associated with low-dose methotrexate therapy for rheumatoid arthritis. MATERIAL AND METHODS: We present a case report of a 64-year-old woman with rheumatoid arthritis who had received low-dose methotrexate therapy for 16 months in whom blurred vision occurred. An ophthalmologic examination was performed, and prednisone was administered. Subsequently, she complained of sore throat, weakness, and fever. An axillary lymph node biopsy and immunologic studies were done. RESULTS: Funduscopic examination revealed severe bilateral choroidal thickening. Findings on the biopsy disclosed a large cell, B-cell phenotype non-Hodgkin's lymphoma. Immunologic studies performed on frozen and paraffin-embedded tissue samples showed that the neoplastic cells were positive for CD20 and CD22 and without definite immunoglobulin light chain expression. CONCLUSION: Although the occurrence of lymphoma may be associated with autoimmune diseases, low-dose methotrexate therapy has also been implicated. Because of the increasing use of low-dose methotrexate therapy for classic and juvenile rheumatoid arthritis, an increased risk of lymphoproliferative disease is possible.
8278816	Limitations of randomized clinical trials to recognize possible advantages of combination	1993 Oct	Potential advantages of combination second-line drug therapy in rheumatoid arthritis (RA) may not be detectable in standard randomized controlled clinical trials, despite excellent design and performance. This results from intrinsic limitations of usual clinical studies, such as a short time frame, patient selection, and insufficient numbers of patients. Examples of selected clinical protocols in rheumatic diseases that illustrate these problems are presented. In systemic lupus erythematosus, many well-designed and -performed trials comparing combinations of cytotoxic drugs and corticosteroids with corticosteroids alone were inconclusive. However, combination therapy was superior in three types of studies: a 15-year clinical trial, a pooled analysis of multiple trials, and longitudinal databases of unselected patients. In RA, a 48-week study indicated no differences in results of treatment with auranofin, methotrexate, and the combination of these two drugs. In contrast, a clinical database from 15 rheumatology practices indicates that methotrexate was continued for 5 years by more than 50% of patients, compared with fewer than 10% for auranofin. A subset from the clinical database of courses of second-line drugs over 1 year (rather than 5 years), for only the initial course of a second-line drug (rather than any course), was examined. Using these selected data, which mimic the conditions of the clinical trial, no significant differences were seen in continuation of methotrexate versus auranofin. This observation suggests that intrinsic limitations, including patient selection, insufficient patient numbers, and a short time frame, may render it difficult (or impossible) to document the efficacy of combination therapy in RA using standard randomized controlled clinical trials.
8493585	[A case report--pulmonary cryptococcosis associated with systemic lupus erythematosus and	1993 Feb	A case of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) associated with pulmonary cryptococcosis which was successfully treated with fluconazole (FCZ) and flucytosine (5-FC) is described. A 63-year-old woman who had been treated with steroid for SLE and low dose methotrexate (MTX) for RA was admitted to Jichi Medical School Hospital because of abnormal shadow in the chest X-ray film. Physical examination revealed no abnormality. A chest CT film showed multiple nodular shadows localized in the right lower lobe. An ultrasonically guided trans-cutaneous lung biopsy performed on 10th hospital day established a diagnosis of pulmonary cryptococcosis. Following the treatment with FCZ and 5-FC for a month, her abnormal lung shadows improved and serum cryptococcal antigen level was decreased. A survey of the literature from 1955 to 1990 revealed 44 cases of SLE associated with cryptococcosis in Japan, in addition to our case, most of whom were on corticosteroid therapy. The majority of patients were young women, representing the usual population of patients with SLE. 34 of these patients had cryptococcal meningitis; 22, pulmonary cryptococcosis; 6, sepsis; 6 cutaneous cryptococcosis. Twenty patients died. Deep fungal infections should be considered whenever patients with SLE have fever of unknown origin, diffuse pulmonary infiltrates, or unexplained CNS symptoms.
8717103	Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid art	1996	The objective of this study was to examine longitudinally the tolerability of methotrexate (MTX) treatment at doses exceeding 15 mg/week in an open-label, prospective study. One hundred and eighty-five patients with rheumatoid arthritis were randomized to receive 15 mg or 25 mg MTX per week initially, and were followed over 30 months. Subsequent dose adjustments according to efficacy and tolerability resulted in levelling off of the mean dose at 18 mg/week, and the original treatment groups were combined for a longitudinal study comparing toxic events during months 1-12 and months 13-30. Withdrawals due to side-effects amounted to 17% during months 1-12 and 4% during months 13-30; dose reductions due to side-effects were 9% and 7%, respectively. The annual incidence of gastrointestinal side-effects increased from 26% to 39% (P = 0.05), that of liver enzyme elevation dropped from 43% to 10% (P < 0.001) and haemocytopenia remained stable at 5% and 7%. MTX pneumonitis was only observed during the first year, while airway complaints without evidence of parenchymal lung involvement increased to 10% beyond the first year. Fifty-six patients experienced 65 major infectious episodes over the 30-month period, with the respiratory tract being the most frequent site. This study showed that MTX treatment at doses exceeding 15 mg/week is tolerated over extended period of time. Major toxicity and withdrawals due to side-effects occurred predominantly during the first year of treatment and thus showed a decreasing trend over time, while minor toxic events continued throughout the study with a progressive rate of mucous membrane toxicity. MTX-treated RA appears to be a risk situation for major infection.
7667645	Infections during low-dose methotrexate treatment in rheumatoid arthritis.	1995 Jun	We studied the infection rate in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) in a 6-year open prospective study and in a 12-month randomized double blind trial comparing MTX with azathioprine (AZA) that was followed by a 3-year open prospective study. The literature on infections during low dose MTX in RA was reviewed. We also did a search for therapy-related opportunistic infections in RA and in MTX-treated psoriasis and psoriatic arthropathy patients. In our studies the infection rate during MTX treatment was higher in severe RA than in moderate RA. In severe RA there were often 2 infections simultaneously. The majority of the infections occurred in the first 1.5 years of treatment. There was no difference in the infection rate of MTX and AZA in the comparative trial. In the literature the infection rate was highest in short-term double-blind studies. Opportunistic infections are increasingly reported in RA treated with MTX and rarely with AZA, cyclosporine A, and cyclophosphamide or in MTX treated psoriasis and psoriatic arthropathy. In RA it appears that the initial period of treatment with MTX is the most vulnerable phase for infections, with the exception of opportunistic infections, which are not limited to a certain treatment period. Probably there are more MTX-associated infections in severe RA than in moderate RA.
1328631	Effects of a single dose of methotrexate on 5- and 12-lipoxygenase products in patients wi	1992 Jun	The inhibition of 5-lipoxygenase could be involved in the mechanism of action of methotrexate (MTX). We studied 8 patients with active rheumatoid arthritis (RA) immediately before and the day after the first dose of MTX (10 mg intramuscularly). Leukotriene B4 (LTB4) formation by polymorphonuclear leukocytes was significantly decreased (32%, p less than 0.01). This essentially involved released LTB4. A slight decrease was also obtained in omega-oxidation products. Similar results were obtained for plasma LTB4 (30%, p less than 0.02). A non-significant decrease in 5-HETE was noted. Conversely, 12-HETE was not modified. Our results suggest MTX has an effect on the 5-lipoxygenase pathway, particularly at the LTA4 epoxide hydrolase step, since 5-HETE and 6-trans-LTB4 isomers are not involved.
8779790	[Prospective clinical study of the combination therapy of auranofin and methotrexate for r	1996 Jun	In a study to evaluate the usefulness of DMARDs combination therapy for RA, AF and MTX were concurrently given to RA patients who had responded poorly to over three months of monotherapy of either AF or MTX. The study was composed of two stages. In the first stage, patients were concurrently given AF and MTX for six months in order to evaluate the efficacy of combination therapy. In the second stage, patients who had responded to the earlier combination therapy were again put on monotherapy of the additive DMARD. Safety evaluation was conducted with 126 patients, and both efficacy and utility were evaluated in 100 patients. Lansbury index for RA significantly improved in both groups of patients starting with the AF and followed by the MTX combination (Group I) and those who started with MTX alone followed by the AF combination (Group II). The ratio of patients who achieved slight improvement or better in the overall improvement rating was significantly higher in Group I at 74.6%, vs. 51.1% in Group II patients. Ten patients (16.9%) and 2 patients (4.9%) were switched to their additive DMARD monotherapy of MTX and AF respectively, having responded to the combination therapy in stage I with slight improvement or a better rating. Adverse events were observed in 44 patients (34.9%), but the combination therapy neither increased the incidence of adverse events nor caused new adverse events. Combination therapy of AF and MTX appeared to be useful both in terms of efficacy and safety for patients who have experienced the dwindling effect of monotherapy.
8651964	Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are rece	1996 Jun	OBJECTIVE: To assess the frequency and clinical features of an acute febrile toxic reaction (AFTR) in patients with refractory rheumatoid arthritis (RA) receiving combined therapy with methotrexate (MTX) and azathioprine (AZA). METHODS: A cohort of 43 RA patients being treated with MTX/AZA combination therapy were studied. In all of them, RA had been refractory to single-therapy disease-modifying antirheumatic drugs. We analyzed the frequency and clinical features of AFTR, which consisted mainly of the development of fever, leukocytosis, and cutaneous leukocytoclastic vasculitis when AZA was added to the MTX regimen. RESULTS: Four of the 43 patients (9.3%) who had been receiving long-term, well-tolerated treatment with MTX (mean +/- SD 375.5 +/- 159.5 days, range 227-561 days) developed AFTR shortly (mean +/- SD 25.7 +/- 13.6 days, range 17-46 days) after the addition of AZA to the regimen. The AFTR resolved rapidly (3 +/- 1.4 days) after discontinuation of AZA and MTX. In 2 cases, rechallenge with AZA and MTX was linked to a new flare of AFTR. CONCLUSION: The knowledge of this side effect is particularly important because it mimics a severe infectious complication related to immunosuppressive therapy, and because rechallenge can produce severe toxicity. Most of the new combined therapies for RA do not seem to be more toxic than single-drug treatment. Nevertheless, clinicians should be aware of a possible increase in side effects due to drug interactions or some other unidentified mechanism.
1618240	The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in	1992	We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.
8629827	Methotrexate osteopathy in long-term, low-dose methotrexate treatment for psoriasis and rh	1996 Feb	BACKGROUND: In dermatology and rheumatology, methotrexate is frequently prescribed in low dosages per week; in oncology, high dosages per week are prescribed. Methotrexate osteopathy was first reported in children with leukemia treated with high doses of methotrexate. In animal studies, low doses of methotrexate proved to have an adverse effect on bone metabolism, especially on osteoblast activity. OBSERVATIONS: Methotrexate osteopathy is a relatively unknown complication of low-dose methotrexate treatment. We describe three patients treated with low-dose oral methotrexate in whom signs and symptoms were present that were similar to those found in children treated with high doses of methotrexate. All three patients had a triad of severe pain localized in the distal tibiae, osteoporosis, and compression fractures of the distal tibia, which could be identified with radiographs, technetium Tc 99m scanning, and magnetic resonance imaging. CONCLUSIONS: Methotrexate osteopathy can occur in patients treated with low doses of methotrexate, even over a short period of time. As pain is localized in the distal tibia, it is easily misdiagnosed as psoriatic arthritis of the ankle, but the diagnosis can be correctly made by careful investigation and use of imaging techniques. The only therapy is withdrawal of methotrexate. It is important that more physicians become aware of this side effect of methotrexate therapy, which can occur along with arthritic symptoms.
8793258	Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dos	1996 May	We reviewed the records of 315 patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) and evaluated the conditions contributing to thrombocytopenia. Thirteen out of 315 patients with RA presented with low platelet counts (< or = 100,000/mm3). The age of these patients (51 +/- 12.6 years) did not correlate with thrombocytopenia (r = 0.211, p > 0.05). Thrombocytopenia resulted from coadministration of MTX and NSAID or multiple drug interactions. We observed a significant (r = 0.48, p < 0.05) increase of discontinuation of NSAID's but not of MTX therapy (r = 0.42, p > 0.05) with a mounting weekly dosage of MTX (12.5 +/- 5 mg orally). There was a significant correlation between this weekly dosage of MTX coadministered on the same day with NSAID and thrombocytopenia (r = 0.6, p < 0.05). In most cases (9/13) MTX was not or just temporarily withdrawn. Three of the remaining patients had multiple drug interactions. Reintroduction of low dose MTX treatment in patients having had thrombocytopenia could be performed safely, if thrombocytopenia occurred as a result of concomitant application of MTX and NSAID and no other multiple drug interactions. Preferably, MTX and NSAID should be given to these risk patients on separate days or intervals considering half time clearance of NSAIDs. This procedure has prevented the reoccurrence of thrombocytopenia and controlled further drug interactions of NSAIDs and MTX in our patients.
8803910	The role of anti-malarials in rheumatoid arthritis--the American experience.	1996 Jun	Rheumatoid Arthritis (RA) is a chronic disease with significant morbidity and functional disability. The traditional treatment for RA relied on the use of NSAIDs early in the disease course, followed by disease-modifying agents later. More recently, the disease-modifying anti-rheumatic drugs (DMARDs) have become the mainstay of RA therapy because of the recognition of their superior efficacy/toxicity profile. The antimalarial drugs, chloroquine and hydroxychloroquine, are some of the most commonly used DMARDs in the management of RA. They have been shown to be significantly more effective than NSAIDs alone in several clinical trials, and have a benign toxicity profile. A combination of hydroxychloroquine with methotrexate appears to reduce significantly the hepatic toxicity of methotrexate. In this review, we summarize the efficacy and toxicity profiles of the antimalarial drugs in rheumatoid arthritis.
8624637	In vitro effects of methotrexate on human articular cartilage and bone-derived osteoblasts	1996 Apr	Conflicting data have been published on whether low-dose methotrexate (MTX) treatment of rheumatoid arthritis (RA) is able to slow down radiological joint damage, i.e. retard the destruction of articular cartilage and (subchondral) bone. We studied the effects of MTX on proteoglycan (PG) turnover and interleukin-1 (IL-1)- and RA mononuclear cell (RA-MNC)-induced cartilage damage in human articular cartilage tissue cultures, and the effects of MTX on basal and RA-MNC-influenced proliferation and differentiation of osteoblasts in cultures of human bone-derived osteoblasts. MTX exerted no direct effect on cartilage nor did MTX influence IL-1- or RA-MNC-induced cartilage damage, despite strong suppression of basal as well as mitogen- and antigen-induced RA-MNC proliferation. MTX induced strong inhibition of osteoblast proliferation, but did not significantly interfere with osteoblast differentiation (i.e. alkaline phosphatase activity). RA-MNC-enhanced proliferation and differentiation of osteoblasts were abolished by MTX. These results suggest that if MTX is able to induce retardation of radiological progression in RA, this is not based on an initial direct effect of MTX on cartilage as measured by PG turnover, nor on an initial inhibition of IL-1- or RA-MNC-induced cartilage damage. However, longstanding MTX-induced inhibition of RA-MNC proliferation may lead to reduction of the catabolic activity involved in cartilage destruction. On the other hand, long-term inhibition of osteoblast proliferation may eventually lead to decreased bone formation and osteopenia. Whether this will turn out to be a problem of clinical importance in the treatment of RA has to be established.
8864317	Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: phar	1996 Aug	1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite > 6 months of SASP treatment. 2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis. 3. Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml-1, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t1/2,z: 4.3 +/- 1.1 vs 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 25.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h-1. CLR/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) l h-1. All P values were > or = 0.3. 4. A weak correlation existed between the change of ESR and the MRT, the t1/2,z and the V/F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05 < P < 0.1). 5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables on MTX.