Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate

PURPOSE: Herpes zoster occurred in nine patients with methotrexate-treated rheumatoid arthritis. We compared these patients to a large group of methotrexate-treated rheumatoid arthritis patients in order to uncover potential factors explaining the occurrence of herpes zoster. PATIENTS AND METHODS: Data from 187 patients taking methotrexate were reviewed and compared with data from another nine patients who developed herpes zoster while taking the drug for rheumatoid arthritis, all from the same university-based arthritis clinic. Literature pertinent to infection in rheumatoid arthritis patients treated with methotrexate is reviewed. RESULTS: Herpes zoster occurred in 14.5 cases per 1,000 patient-years in our methotrexate-treated rheumatoid arthritis patients, as compared with the general population incidence of 1.3 to 4.8 cases per 1,000 patient-years. The infection was unrelated to duration of methotrexate usage, prednisone treatment, or the co-existence of diabetes mellitus, but appeared to occur in patients with high titers of rheumatoid factor and an overall longer duration of rheumatoid arthritis. There were no cases of systemic dissemination or recurrence of herpes zoster despite 27.4 years cumulative follow-up on continued methotrexate therapy. CONCLUSIONS: Herpes zoster may occur more frequently in patients with rheumatoid arthritis treated with low-dose methotrexate than in the general population. Herpes zoster in rheumatoid arthritis patients treated with methotrexate appears to be self-limited, benign, and statistically related to methotrexate use in the presence of longer-term rheumatoid disease.     

Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab

OBJECTIVE: This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage METHODS: NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. RESULTS: The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. CONCLUSION: The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.     

Vertebral bone mineral density changes in female rheumatoid arthritis patients treated with low-dose methotrexate

OBJECTIVE: To assess vertebral bone mineral density (BMD) changes in rheumatoid arthritis (RA) patients taking low-dose methotrexate (MTX). METHODS: We evaluated in a 2-year, longitudinal study female RA patients, who had recently started a disease-modifying antirheumatic drug (DMARD), divided into two groups: group A, receiving MTX, and group B, receiving other DMARDs. Lumbar spine BMD was assessed at baseline and every year; RA activity was assessed every 3 months. RESULTS: Sixty-two patients were enrolled in the study; 40 completed the follow-up period: 22 of group A, and 18 of group B. The results after 2 years showed that both groups lost bone significantly vs baseline (p < 0.001) in a comparable fashion: group A (mean +/- SD) -3.9 +/- 4.9% vs group B -3.0 +/- 3.7% (p = NS). The patients who showed active disease lost significantly (p < 0.05) more bone (-5.5 +/- 3.8%) than those with less active disease (-1.1 +/- 3.6%), independently of their DMARD. CONCLUSION: Low-dose MTX in RA does not seem to exert relevant effects on trabecular bone.     

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.     

Pharmacokinetics and efficacy of low-dose methotrexate in patients with rheumatoid arthritis

This article evaluates the relationship between the pharmacokinetics of methotrexate (MTX), its efficacy in the treatment of rheumatoid arthritis (RA), and serum folic acid (FA) levels. The pharmacokinetics of MTX was studied in 29 patients with RA treated with low-dose MTX. The weekly dose of MTX was given orally at 2–4mg every 12h over a period of 24–36h. Blood samples were taken 4h after the first administration in any given week. A Bayesian method was used to estimate individual MTX pharmacokinetic variables. We then investigated the efficacy of MTX and the serum FA levels in these patients. We examined C-reactive protein levels (CRP) and the erythrocyte sedimentation rate (ESR), and analyzed the values obtained before and after MTX treatment in order to evaluate the efficacy of the MTX treatment. The degree of improvement in CRP and ESR was significantly correlated with the length of time the MTX concentration–time curve remained above 0.02µM in one week. Furthermore, the degree of improvement in CRP was also significantly correlated with the area under the concentration–time curve (AUC) for MTX. These results suggest that serum MTX measurements could be useful in determining individual patient regimens.     

Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France

A national prospective study was designed to collect all cases of lymphoma appearing in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) throughout France over a period of 3 years. A total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin lymphoma (NHL), 3 of which were associated with the presence of Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin disease (HD), 5 of them associated with EBV. Among the 8 patients who were treated by MTX withdrawal alone, 3 underwent remission, but 2 of them had a relapse, the third patient with clonal EBV-associated large granular lymphocytes T-cell NHL remaining alive in complete remission. The estimated annual incidence rate of NHL in RA patients treated with MTX was 33.3.10(-5) (0-80.5) among men and 16.7.10(-5) (0-33.3) among women. There was no significant excess with the French population as a comparison: the standardized mortality ratio (SMR) adjusted for age and sex was 1.07 (0.6-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10(-5) (0-70.1) and 2.8.10(-5) (0- 9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P <.001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.     

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.     

Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study

Abstract

The aim of this study was to assess if low-dose tacrolimus is efficacious for the treatment of rheumatoid arthritis (RA) when combined with methotrexate (MTX). The clinical courses of 32 RA patients who received tacrolimus plus MTX were analyzed retrospectively. Disease activity and clinical response were evaluated by DAS28 (disease activity score of 28 joints) and EULAR (European League Against Rheumatism) response criteria. Tacrolimus was started at 1 mg/day in five patients, 1.5 mg/day in 24 patients, and three mg/day in 3 patients. At six months, tacrolimus was continued at 1–2 mg/day in 27 of 32 patients, but was discontinued in five cases who showed no or inadequate response. Of the 32 patients, 47% were evaluated as having a moderate or good response at one month of tacrolimus therapy, and 72% at six months. No serious adverse events were observed. Our results suggest that the addition of tacrolimus at low dose to MTX for the treatment of patients with moderately active RA appears to be highly efficacious. Further studies are required for the appropriate use of this expensive immunosuppressant in the treatment of RA.     

Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study

The aim of this study was to assess if low-dose tacrolimus is efficacious for the treatment of rheumatoid arthritis (RA) when combined with methotrexate (MTX). The clinical courses of 32 RA patients who received tacrolimus plus MTX were analyzed retrospectively. Disease activity and clinical response were evaluated by DAS28 (disease activity score of 28 joints) and EULAR (European League Against Rheumatism) response criteria. Tacrolimus was started at 1 mg/day in five patients, 1.5 mg/day in 24 patients, and three mg/day in 3 patients. At six months, tacrolimus was continued at 1-2 mg/day in 27 of 32 patients, but was discontinued in five cases who showed no or inadequate response. Of the 32 patients, 47% were evaluated as having a moderate or good response at one month of tacrolimus therapy, and 72% at six months. No serious adverse events were observed. Our results suggest that the addition of tacrolimus at low dose to MTX for the treatment of patients with moderately active RA appears to be highly efficacious. Further studies are required for the appropriate use of this expensive immunosuppressant in the treatment of RA.     

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.     

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.     

Immunologic studies of rheumatoid arthritis patients treated with methotrexate

Immunologic functions of peripheral blood mononuclear cells were studied in rheumatoid arthritis (RA) patients treated with methotrexate (MTX). Spontaneous IgM rheumatoid factor (IgM-RF) synthesis by unstimulated cultured blood mononuclear cells was seen in only 3 of 18 MTX-treated patients, compared with 31 of 54 RA patients who were not receiving long-acting drugs. Total IgM production by unstimulated cultured mononuclear cells, pokeweed mitogen-induced antibody synthesis, and plasma levels of IgM-RF were also lower in MTX-treated patients than in other RA patients. The numbers of circulating B cells, T4 and T8 cells, the T4:T8 cell ratio, and mitogen-induced proliferation indices were similar in MTX-treated and non-MTX-treated patients. Eleven additional patients were studied prospectively after initiation of MTX therapy. All showed significant decreases in spontaneous IgM-RF synthesis, with declining IgM-RF:IgM ratios, including all of the 9 who were studied during the first 24 hours of treatment. The results indicate that MTX has rapid effects on IgM-RF synthesis, and this action might be associated with its therapeutic efficacy in RA.     

Alendronate in rheumatoid arthritis patients treated with methotrexate and glucocorticoids

Rheumatoid arthritis (RA) is a systemic inflammatory disease. Along with synovial joint inflammation, extra-articular involvement is a common feature of RA. Periarticular and generalized osteoporosis are seen both as an extra-articular feature of the disease itself and due to various medications like glucocorticoids and methotrexate (MTX). In this study, we investigated the effects of oral alendronate in RA patients treated with MTX and prednisolone by comparing the effects of “alendronate+calcium” and “only calcium” on bone mineral density (BMD). Fifty RA patients classified according to American Rheumatism Association (ARA) criteria were included in the study. The control group consisted of 20 postmenopausal osteoporotic patients. The RA patients were divided randomly into two groups. All patients were started on MTX 7.5 mg/week, 2.5-mg daily folic acid, and 7.5-mg daily prednisolone. The first group, consisting of 25 female RA patients, was also given 10-mg daily alendronate and 1000-mg daily calcium. The second group also consisted of 25 female patients and was given only 1000-mg calcium per day. The postmenopausal control group was given daily 10-mg alendronate and 1000-mg calcium. Bone mineral densities were measured by dual-energy x-ray absorptiometry (DEXA) and again at the end of the sixth month. At the end of the study, RA patients given only calcium had reduced mean BMD, and patients treated with alendronate and calcium showed increased mean BMD almost in all regions. This increase was significant in the L2 and L1–4 total regions. In postmenopausal osteoporotic patients, we saw statistically significant increases in BMD in all regions. The increase in BMD values in RA patients treated with alendronate was smaller than in those of the control group of postmenopausal osteoporosis patients. In conclusion, RA itself has a risk factor for osteoporosis in addition to the risks of the medications like corticosteroids and MTX. In the prevention and treatment of RA-associated osteoporosis, alendronate and calcium therapy is effective and well tolerated. Received: 16 June 2000 / Accepted: 20 August 2000     

Leukoencephalopathy induced by low-dose methotrexate in a patient with rheumatoid arthritis

We report a patient with rheumatoid arthritis (RA) who developed leukoencephalopathy while being treated with low-dose methotrexate (MTX). She suddenly developed loss of recent memory and left homonymous hemianopsia ascribable to the bilateral but right-predominant occipitotemporal lesions. Intravenous administration of dexamethasone and cessation of MTX quickly relieved her clinical symptoms. Low-dose MTX-induced leukoencephalopathy is a rare complication in RA, but is important with regard to the possibility of serious neurological sequellae.     

Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate

Because of a previously observed plateau of clinical response after long-term methotrexate (MTX) therapy for rheumatoid arthritis (RA), we investigated whether such treatment might lead to acquired resistance to the drug. We studied the activity of dihydrofolate reductase (DHFR) (the target enzyme of MTX) in peripheral blood mononuclear cells of 11 RA patients who had been treated with MTX for a median of 43 months. The enzyme levels were markedly increased compared with levels found in the cells of 6 RA patients treated with other slow-acting drugs. Quantitative dot-blot analysis of DNA from 7 of these patients showed no evidence of DHFR gene amplification. No correlation was observed between increased levels of DHFR and either response to therapy or to the weekly MTX dosage. Phytohemagglutinin-stimulated peripheral blood lymphocytes from 6 patients with increased levels of DHFR showed no evidence of MTX resistance in vitro. The increased DHFR levels may result from binding of MTX to the enzyme, which may block the normal degradation pathways; they do not appear to be a marker of impending drug resistance.