Lymphoma developing in a patient with rheumatoid arthritis taking methotrexate

Summary We report one case of non-Hodgkin lymphoma in a patient, with a 30-year history of rheumatoid arthritis, taking low dose methotrexate weekly over a 10-month period. The mild immunosuppression that occurs with methotrexate therapy probably places patients with rheumatoid arthritis at added risk of developing lymphoproliferative diseases, but coincidence cannot be excluded.     

Every-other-week methotrexate in patients with rheumatoid arthritis

Objective. To determine if patients with rheumatoid arthritis (RA) that is stable with weekly methotrexate (MTX) therapy could be switched to an every-other-week regimen of MTX. Methods. Forty-seven patients with classic or definite RA who had received MTX for at least 8 months were studied. Clinical measurements consisted of the number of tender and swollen joints, physician and patient global evaluation of disease activity on a 5-point scale, grip strength, patient evaluation of pain, morning stiffness, and the interval to onset of fatigue from time of awakening. Laboratory measures included the erythrocyte sedimentation rate (ESR), rheumatoid factor, C-reactive protein (CRP), and baseline serum folate levels. Uptake of MTX was measured with tritiated thymidine from peripheral blood mononuclear cells (PBMC) from patients ex vivo. Serum measures of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNFα) were performed in sera, and TNFα was also measured on PBMC supernatants. Results. Twelve of the 23 patients receiving every-other-week MTX (52%) were able to complete 6 months of this treatment without experiencing a disease flare. Eleven of the 23 patients receiving every-other-week MTX (48%) withdrew from the study before completing 6 months of treatment, because of a flare. No significant differences in clinical or laboratory parameters were seen when the 24 patients receiving weekly MTX were compared with the 12 patients in the every-other-week MTX group who successfully completed 6 months of the study. None of the changes in serum cytokine levels were significantly different between the patients receiving MTX weekly versus those receiving it every other week, and changes in ESR and CRP did not differ between groups. Age, sex, RA disease duration, MTX weekly dose or duration, baseline joint counts, or serum folate status did not predict a flare. Tritiated MTX uptake did not differ between groups. Conclusion. Some patients with RA that is stable on weekly dosing are able to change to every-other-week dosing without experiencing a flare in their disease activity.     

Risk taking in patients with rheumatoid arthritis

SIR, We read with interest the paper entitled ‘Risk takingin patients with rheumatoid arthritis: are the risks of haemopoieticstem cell transplantation acceptable?’ by Snowden et al.[1]. They cited two previous studies [2, 3] demonstrating thatrheumatoid patients were willing to     

The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate

Objective. To assess the cost-effectiveness of liver biopsy in monitoring rheumatoid arthritis (RA) patients for methotrexate (MTX)–induced cirrhosis. Methods. A decision analytic model was used to compare a strategy of no biopsy versus strategies of biopsy after 5 years or 10 years of MTX treatment. Results. Biopsy after 5 years of MTX treatment had a cost-effectiveness ratio of $1,891,830 per year of life saved, while biopsy after 10 years of treatment had a cost-effectiveness ratio of $52,374 per year of life saved. Sensitivity analyses revealed that the cost-effectiveness of biopsy was most dependent on the probability of cirrhosis. Conclusion. Liver biopsy to monitor for MTX-induced cirrhosis in RA patients is not cost effective after 5 years of treatment, and even biopsy after 10 years has a high cost.     

Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis

Objective. To assess the risk of serious liver disease in patients with rheumatoid arthritis (RA) taking methotrexate (MTX). Methods. We surveyed members of the American College of Rheumatology to determine previous use of MTX in the treatment of rheumatoid arthritis and to identify cases of cirrhosis and liver failure. Cases were confirmed by review of pathology specimens, findings from diagnostic testing, and clinical presentations. A case—control study was then conducted to ascertain prognostic factors. Case and control medical records were reviewed for information on MTX therapy as well as other possible determinants of serious liver disease. Results. Twenty-four cases of cirrhosis and liver failure were identified, giving a 5-year cumulative incidence of ˜ 1/1,000 treated patients. Six of the 24 patients had died: 4 died of the initial liver disease, 1 of hepatic complications of another illness, and 1 of unrelated causes. Two patients continue to have active liver disease. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease. Conclusion. Serious liver disease is an uncommon, age- and dose-related complication of low-dose MTX therapy for RA.     

Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate.

We describe the occurrence of a lymphoma in a patient with rheumatoid arthritis (RA) taking weekly oral pulse methotrexate (MTX) in low doses for 33 months. This occurrence may be coincidental. There may be an increased incidence of lymphoma in RA not treated with immunosuppressive medications. However, the increasing use of MTX warrants reporting unusual events, especially malignancy. It is possible that even the mild immunosuppression that occurs with MTX therapy places patients with RA at added risk for developing lymphoproliferative diseases.     

Factors influencing length of time taking methotrexate in rheumatoid arthritis

OBJECTIVE: Duration of therapy has been suggested to represent a measure of effectiveness. Life table analyses of therapy with methotrexate (MTX) in rheumatoid arthritis (RA) have indicated a longer duration than with other drugs. However, individual patients continue taking MTX for different periods of time. We assessed the influence of patient variables at treatment onset upon subsequent duration of MTX therapy. METHODS: Patients with RA (n = 437) from 8 North American databank centers beginning MTX therapy after January 1, 1988, were followed prospectively. Age at onset of MTX treatment, sex, years of education, age at onset of disease, years with disease, number of comorbid conditions, number of disease modifying antirheumatic drugs (DMARD) and nonsteroidal antiinflammatory drugs (NSAID) taken just prior to MTX. disability level, pain, and global assessment prior to starting MTX were used in univariate Kaplan-Meier analyses to predict number of months taking MTX alone. An index that divided the patients into risk strata for predicting duration of therapy was constructed to be clinically useful. RESULTS: The median number of months continuing MTX without addition of other DMARD was 41 months and the median for the total course taking MTX was 52 months. The retention rate was lowest for patients with the most negative initial health state. High level of initial pain, long duration of disease, and not using a DMARD just prior to MTX were associated with low retention rate and can be used to predict expected durations of MTX treatment ranging from 17 to 52 months. For practical guidance in clinical decisions an index was computed based on the predictor variables: level of initial pain, duration of disease, and number of DMARD; this index identifies subgroups with very different durations taking MTX alone. Disease duration at baseline was strongly related to time taking MTX alone and could therefore also be used as a simplified rule in clinical work. CONCLUSION: Expected duration of MTX treatment is influenced by clinical variables, and these may suggest those patients likely to have more or less satisfactory experiences with MTX. The time taking drug alone (therapeutic segment) may be a more logical and sensitive indicator of effectiveness than the total course on the medication.     

Aspirin alters methotrexate disposition in rheumatoid arthritis patients.

Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis.     

Treatment of rheumatoid arthritis with methotrexate in Congolese patients

Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) but data concerning the effectiveness of treatment with this compound are lacking in the Congolese population. In the present study, the evolution of RA in Congolese patients on MTX treatment is reported from before disease-modifying antirheumatic drug (DMARD) initiation till 20 months later. All consecutive DMARD-naïve RA patients (ACR 1987 criteria) attending the rheumatology unit of the University Hospital of Kinshasa from January 2008 to September 2010 were included. All were treated with MTX (started at 7.5 mg/week) and bridging steroids (started at 30mg/day). Treatment adaptations of MTX and concomitant drugs are reported as well as evolution of disease activity (DAS28-ESR), functionality (Health Assessment Questionnaire), radiological damage, and safety over 20 months. Of 98 patients recruited, more than one third were lost at follow-up. A follow-up visit at 20 months was available for 51 patients. These 48 women and 3 men had a mean age of 51.2?±?13 years and a mean delay from symptom onset till their first visit of 3.2 years. At 20 months, the average MTX dose was 9.7 mg weekly. A second DMARD was added in three patients. The average dose of prednisone at 20 months was 7.5 mg daily. A significant improvement of DAS28 and functional disability was observed and 35.3 % of patients entered remission (DAS28 <2.6). A progression of X-ray damage was observed in one third of patients. Two patients had to stop MTX because of severe side effects and two patients developed diabetes. Methotrexate and bridging steroids therapy is effective also in sub-Saharan Africa but the average weekly MTX dose remains low. Implementation of a regular follow-up is a major issue.     

Histopathologic findings in the liver of rheumatoid arthritis patients treated with long-term bolus methotrexate

Twenty-three patients with severe rheumatoid arthritis were treated with oral methotrexate (MTX) for more than 10 years. MTX was given as a bolus of 5-15 mg/week; the total cumulative dose ranged from 4,690 mg to 10,230 mg. Liver biopsies were performed on 21 of the patients to assess possible fibrosis and cirrhosis. Grade I histopathologic changes were found in 13 of the 21 biopsy samples, grade II changes were found in 3, and grade IIIA changes (mild fibrosis) were found in 5 specimens. None of the biopsy samples showed cirrhosis. Repeat biopsies were performed on the 5 patients with grade IIIA changes while they were still taking MTX. No progression of the fibrosis was noted. Two of the 5 samples, however, were graded IIIB because of portal and perilobular inflammation. Our findings support the premise that prolonged administration of oral MTX, when given as a weekly bolus at a low dose, does not cause cirrhosis or severe fibrosis in the rheumatoid arthritis patient who does not abuse alcohol.     

Purine enzymes in patients with rheumatoid arthritis treated with methotrexate

OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.     

Intestinal absorption in patients with rheumatoid arthritis treated with methotrexate

Summary Twelve patients with rheumatoid arthritis treated for at least 12 months with methotrexate and 11 matched rheumatoid arthritis controls underwent a standard d-xylose absorption test. No patients had any pre-existing clinical of biochemical evidence of malabsorption. No significant difference was observed in the 1 hour plasma d-xylose estimation between methotrexate treated patients and controls. The 2 to 5 hour urinary excretion ratio, however, was significantly lower in the methotrexate-treated group compared with controls indicating a minor degree of malabsorption. Six of the methotrexate treated patients and 5 of the controls underwent endoscopic duodenal biopsy but neither group demonstrated any significant histological changes. In conclusion, methotrexate therapy in patients with rheumatoid arthritis produces mild intestinal malabsorption.     

In vitro rheumatoid factor synthesis in patients taking second-line drugs for rheumatoid arthritis.Independent associations with disease activity

Rheumatoid arthritis (RA) patients whose unstimulated peripheral blood mononuclear cells produce high levels of IgM rheumatoid factor (IgM-RF) in vitro have more severe disease activity. RA patients being treated with second-line agents, including gold salts, penicillamine, or methotrexate, tend to be low producers or nonproducers of IgM-RF in vitro. The possibility that low production or nonproduction of IgM-RF in vitro may be explained by treatment with second-line agents alone, irrespective of disease activity, was analyzed in 133 RA patients whose disease status was assessed by multiple laboratory and clinical measures. The results indicate that treatment with second-line agents and in vitro IgM-RF synthesis are independently associated with disease activity.     

Radiographic assessment of disease progression in rheumatoid arthritis patients treated with methotrexate or minocycline

Radiographic studies of methotrexate (MTX) treated and minocycline treated patients with rheumatoid arthritis (RA) are reviewed. A formal metaanalysis of publications of RA treated with MTX was undertaken at the time when MTX was used for patients with established RA. Thus the conclusions of that metaanalysis may not be applicable to patients treated with MTX earlier in the course of their disease. On the other hand, there are no sufficient data to conduct a formal metaanalysis of patients with RA treated with minocycline.     

A debate: should patients with rheumatoid arthritis on methotrexate undergo liver biopsies?

The question of whether it is appropriate to perform liver biopsies in rheumatoid arthritis patients receiving long-term weekly methotrexate therapy is debated. This debate includes a detailed discussion of the literature to support the debaters' respective views. Points made in favor of biopsy include (1) the significant prevalence of hepatic abnormalities in psoriatic patients; (2) the need to continue administration of the drug to sustain a clinical response; (3) the high incidence of elevations in aspartate amino-transferase, which correlate significantly with hepatic histological outcome; and (4) the fact that the rheumatology community has had relatively short experience with the widespread use of the drug. Arguments against biopsy include (1) the poorly defined specific role of methotrexate in the development of hepatic histological abnormalities; (2) the nonquantitative histological grading system, which makes precise assessment of progression in hepatic disease difficult; (3) the poorly defined role of other factors in the progression of hepatic changes in patients taking methotrexate; and (4) the cost and potential morbidity of the procedure itself. The role of the hepatic Ito cell in the development of fibrosis is also discussed. The protagonists agree on the need to continue studies of liver biopsy tissue from rheumatoid arthritis patients receiving methotrexate to better define this key issue.