Dietary intake and circulating vitamin levels of rheumatoid arthritis patients treated with methotrexate

The nutrient intakes and circulating vitamin levels of 32 patients with rheumatoid arthritis who were treated with methotrexate were evaluated over a 6-month period. Dietary data were obtained and blood was drawn prior to the initiation of and following 12and 24 weeks of methotrexate therapy. More than 50% of the patients had food intakes providing less than 67% of the recommended dietary allowance for zinc, vitamin E, foh'c acid, pyridoxine, qnd magnesium. Patients 51 years or older had better nutrient intakes than patients less than 51 years. Of the patients, 22% consumed vitamin supplements at thetime they were recruited for the study. Mean circulating vitamin levels measured over the6-month period were within normal limits. Our findings agree with previously published reports that patients with rheumatoid arthritis, particularly the subpopulation taking methotrexate, consume diets that are marginal in some nutrients. Additional research needs to be done to identify more sensitive nutrient assays and to establish more definitively the nutrient needs of patients with rheumatoid arthritis taking several therapeutic agents.     

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.     

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.     

Five year clinical evaluation of treatment efficacy with methotrexate in patients with rheumatoid arthritis

The objective of this study was to determine long term efficacy and safety of low dose methotrexate (MTX) in treatment of rheumatoid arthritis (RA). Thirty patients receiving MTX for RA were prospectively studied over a mean treatment period of 60 months. Standard clinical and laboratory measures of disease activity were assessed by the same investigator at baseline, and at 3, 6, 24, and 60 months. The occurrence of adverse reactions was noted. Initially MTX was given orally 7.5 mg once a week. In the course of the observation the dose ranged between 5 and 15 mg/week. 13 patients (43%) completed 5-years study. Treatment with MTX was stopped due to adverse events in 4 cases, inefficacy in 7 patients, poor compliance and fear of toxicity in 3 patients and death in 3 patients. The factors related to their death were unrelated in all 3 cases to study MTX therapy. In 13 patients who completed 60 months of therapy, a significant improvement was noted comparing to baseline in 9 out of 12 clinical disease variables and acute phase reactants. There was also a significant decrease in the mean daily dosage of NSAIDs. Adverse events occurred in 64% of the patients, but only 13% of the patients discontinued MTX permanently. The side effects occurred more often in older patients. RA patients treated for five years with MTX showed statistically significant clinical improvement and decrease of inflammation parameters. MTX treatment may be helpful also in patients with advanced forms of RA.     

Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase epstein-barr virus load in patients with rheumatoid arthritis

OBJECTIVE: We previously demonstrated that patients with rheumatoid arthritis (RA) have a 10-fold systemic Epstein-Barr virus (EBV) overload, very similar to that observed in healthy organ transplant recipients. Our objective was to monitor EBV load over time in patients with RA receiving methotrexate, infliximab, or etanercept to detect possible immunosuppression-associated EBV dysregulation, as described in posttransplant lymphoproliferative disease. METHODS: The EBV load in the peripheral blood mononuclear cells (PBMCs) from 19 patients receiving methotrexate, 68 patients receiving infliximab, and 48 patients receiving etanercept was monitored for durations ranging from 6 months to 5 years using a real-time polymerase chain reaction assay previously developed for that purpose. The effect of treatment duration on EBV load and the link between the Disease Activity Score in 28 joints and EBV load were analyzed by generalized estimating equations. RESULTS: Methotrexate tended to decrease EBV load over time, but this did not reach significance. Tumor necrosis factor alpha (TNFalpha) inhibitors did not significantly modify EBV load over time. Finally, high disease activity was significantly associated with high EBV load. CONCLUSION: Long-term usage of methotrexate or TNFalpha inhibitors in patients with RA does not significantly influence EBV load in PBMCs.     

Infliximab but not methotrexate induces extra-high levels of VLDL-triglyceride in patients with rheumatoid arthritis

OBJECTIVE: Tumor necrosis factor (TNF-alpha), a pivotal inflammatory cytokine, is known to induce proatherogenic changes in the lipid profile and may increase the cardiovascular risk of patients with rheumatoid arthritis (RA). We examined the effects of anti-TNF-alpha antibody (infliximab, IFX) compared with methotrexate (MTX) on lipid profiles in patients with RA. METHODS: We selected retrospectively all patients with refractory RA (n = 32) who achieved a successful outcome (DAS-28 score < 2.6) in 6 months with IFX treatment, and control groups of age- and sex-matched patients with active RA treated with MTX and healthy participants. We traced fasting serum levels of total cholesterol (TCHO) and triglyceride (TG) for 6 months and used an online dual enzymatic method for simultaneous quantification of cholesterol (CHO) and TG by high performance liquid chromatography (HPLC). RESULTS: Mean C-reactive protein levels (baseline 4.5) fell to below 1 in 6 months. MTX treatment elevated and normalized TCHO and TG levels. IFX treatment, however, preferentially induced extra-high TG levels. HPLC analyses identified similar CHO profiles between patients treated with IFX or MTX, but IFX selectively induced a huge VLDL-TG peak. Statins successfully controlled these extra-high TG levels. CONCLUSION: In patients successfully treated with IFX or MTX, CHO levels were elevated and normalized, but IFX treatment preferentially induced extra-high levels of VLDL-TG. Thus, there is differential regulation of the lipid profile between IFX and MTX, necessitating careful attention to TG levels with IFX treatment.     

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.     

Omeprazole treatment does not affect the metabolism of caffeine

This study was performed to investigate the possible influence of repeated omeprazole dosing on the metabolism of caffeine, which has been shown to reflect the activity of one specific enzyme within the hepatic cytochrome P450 family, P450IA2. Ten healthy, nonsmoking young men participated in this placebo-controlled double-blind trial. Each subject was given omeprazole, 20 mg, every morning for 1 week and placebo every morning for 1 week in random order and separated by a 2-3 week washout period. On the sixth and seventh days of each period urine was collected twice daily, and urinary metabolites of caffeine were determined by high-performance liquid chromatography. The urinary metabolite ratio of three paraxanthine 7-demethylation products relative to a paraxanthine-hydroxylation product corresponds to caffeine clearance and, therefore, to P450IA2 activity. This calculated ratio was 4.8 (95% confidence interval, 3.9-5.6) in the placebo and 4.6 (95% confidence interval, 3.6-5.5) in the omeprazole period. These results show that the metabolism of caffeine was unaltered following omeprazole treatment, indicating that omeprazole treatment has no influence on cytochrome P450IA2 activity in the clinical situation.     

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.     

Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis

OBJECTIVE: To compare the clinical efficacy of methotrexate and tolerance to the drug in patients with rheumatoid arthritis who were switched from intramuscular to oral administration because of a shortage of the intramuscular preparation. METHODS: 143 patients were switched from intramuscular to oral methotrexate. Of these, 47 were switched back to the intramuscular form. A multiple choice questionnaire was sent by mail to evaluate clinical and biological criteria of efficacy and tolerance. RESULTS: When methotrexate was first switched from intramuscular to oral administration, increased disease activity, exacerbation of morning pain and hand stiffness, duration of morning stiffness, increased joint pain, and increased joint swelling were observed. There was a greater frequency of gastrointestinal symptoms, but without a significant increase in liver abnormalities. When intramuscular methotrexate became available again, 47 of the 143 patients were switched back and were followed for at least three months. On average, disease manifestations were improved and side effects reduced by the switch. CONCLUSIONS: Methotrexate given intramuscularly had improved clinical efficacy with fewer side effects than given orally. Intramuscular methotrexate administration should be considered when rheumatoid arthritis remains active in spite of high dose oral methotrexate.     

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.     

Low dose prednisone does not affect calcium homeostasis or bone density in postmenopausal women with rheumatoid arthritis

To assess whether low doses of prednisone produce generalized alterations in skeletal homeostasis in rheumatoid arthritis (RA), indices of calcium metabolism and bone mineral density (BMD) were measured in 22 women with RA treated without or with prednisone (6.6 mg daily). Ionized and total calcium concentrations, intact parathyroid hormone (PTH) and osteocalcin levels were comparable in the 2 groups. BMD measurements in the lumbar spine, and proximal femur sites including the femoral neck, Ward's triangle, and trochanteric region were not significantly different in patients with RA treated without or with prednisone. In our experience low dose prednisone did not adversely affect indices of mineral metabolism, or bone density in RA.     

Local infectious complications following large joint replacement in rheumatoid arthritis patients treated with methotrexate versus those not treated with methotrexate

We performed a 10-year retrospective analysis of the frequency of local postoperative infectious complications in methotrexate (MTX)-treated rheumatoid arthritis patients who underwent total joint arthroplasty. Sixty patients, who had a total of 92 joint arthroplasties, were receiving MTX. A comparison group of 61 patients with a combined total of 110 total joint arthroplasties were not receiving MTX. The 2 groups were compared for the occurrence of local postoperative infectious complications and poor wound healing. Eight patients in the MTX group experienced a total of 8 complications (8.7% of procedures). In comparison, 5 patients in the non-MTX group experienced a total of 6 complications (5.5% of procedures), a difference that was not statistically significant (chi 2 = 0.816, P = 0.366). Statistical analysis of many other variables revealed none that could be identified as risk factors for postoperative complications. These results suggest that treatment in the perioperative period with weekly low-dose pulse MTX does not increase the risk of local postoperative infectious complications or poor wound healing in rheumatoid arthritis patients who undergo total joint arthroplasty.     

Infliximab does not activate replication of lymphotropic herpesviruses in patients with refractory rheumatoid arthritis

OBJECTIVE: The reactivation of human lymphotropic herpesviruses can be related to the intensity of immunosuppression. We analysed the risk of reactivation of lymphotropic herpesviruses in patients with refractory rheumatoid arthritis treated with an anti-tumour necrosis factor-alpha (TNF-alpha) agent (infliximab). METHODS: Fifteen patients were treated with infliximab (3 mg/kg) at weeks 0, 2 and 6. Samples of both plasma and peripheral blood mononuclear cells (PBMC) were obtained before treatment (week 0) and before each infusion at weeks 2 and 6. Samples were analysed using a multiplex qualitative polymerase chain reaction (PCR) for lymphotropic herpesviruses. Quantification of cytomegalovirus (CMV) viral load (copies/ml) was performed using quantitative PCR. Reactivation was defined as the presence of viral DNA in plasma. Latent infection was defined as the presence of viral DNA in PBMC samples but not in plasma. RESULTS: On baseline, latent CMV infection was detected in eight patients (53.3%), human herpesviruses-6 (HHV-6) in two (13.3%), Epstein-Barr virus (EBV) in seven (46.6%), CMV + HHV-6 in one (6.6%), CMV + EBV in two (13.3%) and HHV-6 + EBV in one (6.6%). Viral reactivation related to infliximab treatment was not observed. There was only one patient who had HHV-6 reactivation, but this was already detected in the baseline sample. CONCLUSIONS: Infliximab treatment does not induce replication of human lymphotropic herpesviruses in patients with rheumatoid arthritis. Thus, herpesviruses prophylaxis would not be indicated in these patients.     

Nonsteroidal anti-inflammatory drug use does not affect short-term endoscopic and histologic outcomes after Helicobacter pylori eradication in patients with rheumatoid arthritis

Abstract

We evaluated the effects of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on endoscopic and histological findings in patients with rheumatoid arthritis (RA) before and after the eradication of Helicobacter pylori infection. Helicobacter pylori (H. pylori) eradication using lansoprazole 30?mg, amoxicillin 750?mg, and clarithromycin 200?mg twice daily for 1 week was conducted in 44 patients (mean age: 56.5 years) with RA. Using the updated Sydney system, endoscopic and histological findings of the greater curvature of the antrum, the greater curvature of the upper corpus, and the lesser curvature of the lower corpus were compared before and after eradication, for a mean follow-up period of 3.5 months. Overall, H. pylori eradication was successful in 32 patients (72.7%). Of these 32 patients, 23 were NSAID users. In the successful eradication group, (1) there was no significant change on endoscopic findings, including gastric erythema and erosion in all three regions irrespective of NSAIDs use; (2) of 17 active ulcers before eradication in NSAIDs users, all healed except for one duodenal ulcer that persisted, where one patient newly developed a gastric ulcer, one developed erosive duodenitis, and two developed reflux esophagitis, all in NSAID users; (3) neutrophil infiltration and chronic inflammation were significantly improved in all three regions after H. pylori eradication irrespective of use of NSAIDs, while atrophic change and intestinal metaplasia did not change. In the eradication failure group; (1) there was no significant change on endoscopic and histological findings in the three regions; (2) two of three ulcers present before eradication on NSAID users persisted even after eradication, and no new cases of gastric ulcer or erosive duodenitis occurred. In conclusion, over a mean follow-up period of 3.5 months, use of NSAIDs in Japanese patients with RA did not impair the healing process of gastric and duodenal ulcers nor did it affect the endoscopic and histological improvements associated with H. pylori eradication.     

Nonsteroidal anti-inflammatory drug use does not affect short-term endoscopic and histologic outcomes after Helicobacter pylori eradication in patients with rheumatoid arthritis

We evaluated the effects of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on endoscopic and histological findings in patients with rheumatoid arthritis (RA) before and after the eradication of Helicobacter pylori infection. Helicobacter pylori (H. pylori) eradication using lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week was conducted in 44 patients (mean age: 56.5 years) with RA. Using the updated Sydney system, endoscopic and histological findings of the greater curvature of the antrum, the greater curvature of the upper corpus, and the lesser curvature of the lower corpus were compared before and after eradication, for a mean follow-up period of 3.5 months. Overall, H. pylori eradication was successful in 32 patients (72.7%). Of these 32 patients, 23 were NSAID users. In the successful eradication group, (1) there was no significant change on endoscopic findings, including gastric erythema and erosion in all three regions irrespective of NSAIDs use; (2) of 17 active ulcers before eradication in NSAIDs users, all healed except for one duodenal ulcer that persisted, where one patient newly developed a gastric ulcer, one developed erosive duodenitis, and two developed reflux esophagitis, all in NSAID users; (3) neutrophil infiltration and chronic inflammation were significantly improved in all three regions after H. pylori eradication irrespective of use of NSAIDs, while atrophic change and intestinal metaplasia did not change. In the eradication failure group; (1) there was no significant change on endoscopic and histological findings in the three regions; (2) two of three ulcers present before eradication on NSAID users persisted even after eradication, and no new cases of gastric ulcer or erosive duodenitis occurred. In conclusion, over a mean follow-up period of 3.5 months, use of NSAIDs in Japanese patients with RA did not impair the healing process of gastric and duodenal ulcers nor did it affect the endoscopic and histological improvements associated with H. pylori eradication.