Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients

The significance of hepatic changes in methotrexate-treated RA patients is unclear at this time. In our group of RA patients, there was a slight increase in the incidence of triaditis and fat during methotrexate therapy. Disease duration greater than or equal to 10 years was associated with increased hepatic triaditis before treatment. Age greater than 50 years was associated with increased hepatic fat before and after treatment. It appears that patients' ages and duration of underlying RA account for some changes, independent of methotrexate therapy. Several of our patients changed from higher to lower histologic grade or had an apparent decrease in fibrosis, fat, or triaditis on the pathologists' reports and the blind readings of the repeat biopsies. This may be explained by sampling error. More importantly, some of these changes may not be of clinical significance. One report of methotrexate-induced cirrhosis in patients with psoriasis demonstrated that in all but one of 14 patients who continued receiving methotrexate the cirrhosis decrease or did not progress. This may also be true of the hepatic fibrosis seen in RA after methotrexate treatment. In this study, there did not appear to be changes seen on pretreatment liver biopsy that were predictive of subsequent fibrosis or cirrhosis. Our data indicate that pretreatment biopsy is unwarranted in a population similar to ours. However, our practice has been to try to avoid methotrexate in patients with diabetes, prior liver disease, alcoholism, or obesity because of previous reports suggesting that these patients are at increased risk for the development of cirrhosis. Only the above-mentioned patient, eventually diagnosed as having cirrhosis, might have been handled differently. Including the study, none of the approximately 700 RA patients in the literature having liver biopsies after methotrexate therapy have developed cirrhosis consequent to its use. Most of these had received a total dose of approximately 1,500 mg in small weekly doses, and alcohol was prohibited. Below this cumulative dose the risk of clinically significant liver damage in carefully selected patients is very low. In view of this experience, the recommendation that RA patients have liver biopsies after 1,500 mg of methotrexate (a holdover from the psoriasis literature) may be too conservative in low-risk RA patients, provided methotrexate is administered weekly and alcohol is prohibited. Recognizing that the absolute need for biopsy is unproven, a more realistic milestone for those choosing biopsy might be after each 2,000 to 2,500 mg.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of abatacept in biologic-naïve patients with active rheumatoid arthritis

This article reviews the efficacy, safety, and tolerability of abatacept plus methotrexate in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate who are naïve to biologic disease-modifying antirheumatic drugs (DMARDs). Data from the randomized, double-blind, placebo-controlled Abatacept in Inadequate Responders to Methotrexate, Abatacept or Infliximab vs Placebo, a Trial for Tolerability, Efficacy, and Safety in Treating Rheumatoid Arthritis, and phase IIb dose-finding trials and their long-term extensions are reviewed. Abatacept plus methotrexate significantly improved clinical responses, physical function, and health-related quality of life compared with methotrexate alone. More patients receiving abatacept plus methotrexate than methotrexate monotherapy achieved a low disease activity state or remission. Radiographic progression of the disease was significantly slowed in the abatacept plus methotrexate arms. Abatacept plus methotrexate was generally well tolerated with no clinically significant safety issues identified. The beneficial effects of abatacept plus methotrexate were sustained long term in extension studies, and no new tolerability or safety issues were evident. Abatacept in combination with methotrexate is an effective, safe, and well-tolerated long-term therapy in biologic-naïve patients with active RA and an inadequate response to methotrexate. Abatacept could be considered as a first-line biologic DMARD in the treatment of RA.     

Antiproliferative effects of methotrexate on peripheral blood mononuclear cells

Methotrexate was added to cultured mononuclear cells from the peripheral blood of normal individuals and patients with rheumatoid arthritis (RA) to study the drug's effects on mononuclear cell proliferation and antibody synthesis. In the presence of methotrexate, marked antiproliferative effects (to levels less than 15% of baseline) were seen with 3H-deoxyuridine, but not with 3H-thymidine, as the marker of cell division. This difference was not due to altered kinetics of proliferation or the presence of salvage nucleotides in the culture medium. The absence of suppression of antibody production preactivated by pokeweed mitogen in vitro and the low levels of suppression of spontaneous IgM rheumatoid factor production by blood mononuclear cells from RA patients suggested a relative resistance of activated cells to the effects of methotrexate. The effects of methotrexate on both cell proliferation and antibody synthesis were completely reversed by the addition of high concentrations of exogenous folinic acid. The results suggest that methotrexate has effects on immunocompetent cells that may contribute to the efficacy of this drug in the treatment of RA and other autoimmune diseases.     

A randomized controlled trial of parenteral methotrexate compared with sodium aurothiomalate (Myochrysine) in the treatment of rheumatoid arthritis

Forty patients with rheumatoid arthritis (RA) were enrolled in a double blind study of 26 weeks duration designed to compare the efficacy and safety of parenteral methotrexate and sodium aurothiomalate (GSTM) in the treatment of RA. All the patients had active RA and none had previously received gold, D-penicillamine or immunosuppressive therapy. Patients were randomized to receive weekly intramuscular (IM) injections of either methotrexate 10 mg or GSTM 50 mg. Two patients taking methotrexate and 7 taking GSTM were withdrawn before 26 weeks. Methotrexate was as effective as GSTM as measured by numbers of swollen or tender joints, morning stiffness, grip strength, pain scale and erythrocyte sedimentation rate. Five patients taking methotrexate and 11 taking GSTM presented side effects (p = 0.05). Total number of adverse reactions was 5 for the methotrexate group and 15 for the GSTM group (p less than 0.01). Our data suggest that low dose IM methotrexate is less toxic and as effective as GSTM for the treatment of RA during the first 6 months of therapy.     

Better effect of methotrexate on C-reactive protein during daily compared to weekly treatment in rheumatoid arthritis

Summary Treatment with methotrexate (MTX) is well established in rheumatoid arthritis (RA), but dosing remains arbitrary as studies on the effect of different dosing schedules are lacking.In a randomised crossover design of 20 patients with RA, the effect of low (2.5mg) oral daily doses of MTX (15 mg weekly) was compared to intermittent weekly dosing (15 mg). C-reactive protein (CRP) values were lower and more stable on daily dosing compared to the significant (p<0.05) changes in CRP observed during treatment with the same weekly dose. It may be postulated that nonresponders or patients with dose-dependent side effects may have clinical advantage from daily MTX dosing if hepatotoxicity and other side effects are not increased.     

Methotrexate-induced pulmonary lymphoma

Methotrexate has proven to be effective in treating rheumatoid arthritis (RA), and is believed to be nononcogenic in the low weekly dose typically employed in the patients with RA. We report, however, a patient with RA in whom a rapidly enlarging diffuse large B-cell lymphoma developed in the left upper lung after weekly treatment with methotrexate for 5 years. The patient had a positive serum IgG for Epstein-Barr virus but a negative in situ hybridization of the resected specimen. Methotrexate therapy was discontinued, and the patient elected for clinical observation instead of chemotherapy or radiation therapy. There has been no clinically detectable recurrence of the lymphoproliferative disorder for 2 years. We believe that methotrexate has an oncogenic potential even in low weekly dosing in a subset of patients with RA and latent Epstein-Barr virus infection. The strongest causal link is demonstrated by the persistent tumor remission after stopping treatment with methotrexate.     

Kombination von BasistherapeutikaVon der individuellen Hoffnung zum gezielten Einsatz

Accumulating evidence suggests that treatment of rheumatoid arthritis (RA) with two or more disease-modifying antirheumatic drugs (DMARDs) is more efficient than single agent therapy. Randomized clinical trials demonstrated the efficacy of various combinations such as methotrexate plus sulfasalazine plus hydroxychloroquine, methotrexate plus ciclosporine or methotrexate plus infliximab, respectively. In contrast to these data, however, most German rheumatologists use combination therapy in a small percentage of patients with active RA. Thus, consensus criteria should be defined when and how to use combination therapy in the treatment of active disease. We suggest that combination therapy should be started if active disease is still present after three months of treatment with a single standard DMARD, mostly methotrexate, plus low dose prednisolone and that combination DMARD therapy should be used before TNF blocking agents.     

Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients

OBJECTIVE: Leflunomide is a novel immunomodulating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration. METHODS: The effects of leflunomide and methotrexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated. RESULTS: Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutrophil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P < 0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis. CONCLUSION: Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.     

Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature

Methotrexate pneumonitis is emerging as one of the most unpredictable and potentially serious adverse effects associated with the use of low dose, pulse methotrexate in treating rheumatoid arthritis (RA). We report 4 new cases of methotrexate pneumonitis in patients with RA and review 6 published cases. A greater than expected proportion of patients had a smoking history, preexisting pulmonary disease and were male. Prognosis was better in those patients treated with corticosteroids.     

The influence of IL-6 polymorphism on efficacy of treatment of rheumatoid arthritis patients with methotrexate and prednisone

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The therapy of RA is associated with application of the drugs modulating the immune response via inhibiting the cytokine production. The common drugs used in RA therapy are methotrexate and prednisone. Recent investigations showed the importance of genetically determined differences in cytokine production in RA activity and therapy. The aim of the present study was to examine the influence of - 174 interleukin-6 (IL-6) promoter polymorphism on the efficacy of treatment of RA patients with methotrexate and prednisone. Polymerase chain reaction amplification was used for analysis of the polymorphism at IL-6 gene. Seventy patients with RA diagnosed according to the criteria of the American College of Rheumatology were investigated. The patients were divided into two subgroups. The first subgroup included patients who have obtained remission for at least 6 months after therapy with methotrexate and glucocorticosteroids. The second subgroup included patients with active disease despite at least 6 months of therapy with methotrexate and glucocorticosteroids. It has been shown that the incidence of remission after therapy with methotrexate and glucocorticosteroids was significantly lower in patients with GG genotype as compared with GC and CC genotypes p< 0.05. We suggest that -174 IL-6 promoter polymorphism may be a genetic risk factor determining the effectiveness of RA treatement with methotrexate and glucocorticosteroids.     

Prospective six year follow up of patients withdrawn from a randomised study comparing parenteral gold salt and methotrexate

OBJECTIVE: To confirm the impression of a better outcome of patients withdrawn from parenteral gold salt therapy compared with those withdrawn from methotrexate. METHODS: Patients with early, active, and erosive RA were randomised for a double blind trial to receive either weekly 15 mg intramuscular methotrexate or 50 mg goldsodiumthiomalate. If the drug had to be withdrawn because of side effects treatment was continued with the other drug in still active disease. Patients with insufficient response were treated with a combination of both drugs. All patients were followed up by an extended clinical and radiographic evaluation. RESULTS: 64 patients each were allocated to methotrexate and gold treatment. After 72 months a complete record was available for 88% of patients. Within the first 36 months 38 patients withdrew from gold treatment (95% because of side effects) and 23 patients withdrew from methotrexate (57% because of side effects). A significant 40% to 70% improvement of all parameters (erythrocyte sedimentation rate, C reactive protein, swollen and tender joints, radiological progression) compared with baseline was observed in patients completing their randomised treatment with gold or methotrexate. The same improvement over three years was seen in patients who withdrew from gold treatment, while patients withdrawing from methotrexate experienced a deterioration of their disease. CONCLUSION: Withdrawals represent the majority of patients in long term drug trials. Patients with early RA stopping gold because of side effects show almost the same sustained improvement as patients continuing gold or methotrexate. Patients withdrawn from methotrexate experience a reactivation of their disease.     

A case of emphysematous pyelonephritis in a patient with rheumatoid arthritis taking corticosteroid and low‐dose methotrexate

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic synovial inflammation. Patients with RA have increased risk of infection; this is related to RA itself or the adverse effects of medication. In this report, we describe a case of emphysematous pyelonephritis in a patient with RA associated with AA amyloidosis and steroid‐induced diabetes mellitus who was taking corticosteroid and low‐dose methotrexate.     

Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs

Modern therapy for rheumatoid arthritis (RA) is based on knowledge of the severity of the natural history of the disease. RA patients are approached with early and aggressive treatment strategies, methotrexate as an anchor drug, biological targeted therapies in those with inadequate response to methotrexate, and "tight control," aiming for remission and low disease activity according to quantitative monitoring. This chapter presents a rationale for current treatment strategies for RA with antirheumatic drugs, a review of published reports concerning treatments in clinical cohorts outside of clinical trials, and current treatments at 61 sites in 21 countries in the QUEST-RA database.     

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.     

Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests

OBJECTIVE: Methotrexate has a well-recognized side-effect of acute hypersensitivity pneumonitis. There is concern about whether chronic pulmonary toxicity can occur with methotrexate treatment. Our objective was to compare chest high-resolution computed tomography (HRCT) findings and serial pulmonary function tests in rheumatoid arthritis (RA) patients on methotrexate with findings for a control group of patients with RA who were not being treated with methotrexate. METHODS: Study patients had an initial chest radiograph, full pulmonary function tests and chest HRCT. Pulmonary function tests were then performed regularly over a 2-yr period. RESULTS: Fifty-five RA patients on methotrexate and 73 control patients with RA were enrolled for the study. Mean dose of methotrexate was 10.7 mg/week (S.D. 2.5 mg/week) and mean duration of treatment at entry into the study was 30 (20) months. Twenty per cent of patients with RA treated with methotrexate had pulmonary fibrosis (PF) on initial HRCT compared with 23% in the control group. When the patients with and without PF were compared, there was no statistical difference in the duration (mean difference -4.18 months, P=0.237) or dose (mean difference -0.8 mg/week P=0.52) of methotrexate therapy. Mean changes after 2 yr in forced expiratory volume, forced vital capacity, diffusion capacity for carbon monoxide and residual volumes were not different in the methotrexate group compared with the control group. CONCLUSION: There is no evidence to suggest clinically, from HRCT assessment or serial pulmonary function tests, that low-dose methotrexate is associated with chronic interstitial lung disease.     

Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis

OBJECTIVE: To identify the proportion of patients with rheumatoid arthritis (RA) in 2 cohorts from Nashville, Tennessee, who met basic criteria for inclusion in 2 important recent clinical trials of anti-tumor necrosis factor alpha (anti-TNFalpha) agents, the early RA (ERA) trial of etanercept versus methotrexate, and the anti-TNFalpha trial in RA with concomitant therapy (ATTRACT) study of infliximab plus methotrexate versus methotrexate. METHODS: Two cohorts of patients, all of whom had met the American College of Rheumatology criteria for RA at some time, were studied. Cohort E (early) comprised 232 patients who were under the care of 5 private practice rheumatologists, whose duration of RA was fewer than 3 years, and who were reviewed for basic inclusion criteria for the ERA clinical trial. Cohort L (long-term) comprised 152 consecutive patients who had been under care at a weekly academic rheumatology clinic for a mean of 4.5 years, and were reviewed for basic inclusion criteria for the ATTRACT study. RESULTS: In cohort E, basic inclusion criteria for the ERA trial were met by 11 of 36 patients (31%) who had not taken methotrexate, 8 of 19 patients (42%) who were at their first visit and had not taken methotrexate, and 37 of all 232 patients (16%). In cohort L, 5% of patients met the basic inclusion criteria for the ATTRACT study. CONCLUSION: Most patients who were seen in routine care in these 2 cohorts did not meet the criteria for inclusion in these 2 important recent clinical trials. The conclusion that anti-TNFalpha therapy has greater efficacy than methotrexate may be valid only in a limited number of patients with the most severe RA. Anti-TNFalpha therapy may be desirable in most patients with RA, but this possibility has not been studied formally. Criteria for inclusion in RA clinical trials might be modified for greater generalizability of results.     

Rheumatoid arthritis and cardiovascular disease

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting approximately 1% of the adult general population. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of their mortality. Patients with RA are at a twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the congeners of accelerated atherosclerosis observed in RA patients. This paper discusses pathogenic mechanisms, effects of methotrexate, tumor necrosis factor antagonists, steroids, and statins, with a perspective on therapy.     

Differential effects of leflunomide and methotrexate on cytokine production in rheumatoid arthritis

BACKGROUND: T cells have a pivotal role in RA. Leflunomide inhibits pyrimidine biosynthesis, to which T cells are especially susceptible, and therefore may have a different cytokine profile than methotrexate. MATERIALS AND METHODS: Serum samples of 100 patients with RA, treated with leflunomide (n = 50) or methotrexate (n = 50), were collected at baseline, after 16 weeks and after 1 year's treatment. Serum levels of interleukin 6 (IL6), and interferon (IFN) gamma were determined by ELISA. Additionally, peripheral blood mononuclear cells (PBMC) of five healthy volunteers and three patients with RA were isolated and the effects of the active metabolite of leflunomide (A77-1726, 0-200 mmol/l) on cell proliferation and on IL6 and IFNgamma production were determined by ELISA. In peripheral blood lymphocytes (PBL) and monocytes (PBM) from two healthy volunteers the effects of A77-1726 on IL6 production were measured by ELISA and PCR. RESULTS: Mean (SEM) serum levels of IFNgamma were significantly reduced after leflunomide treatment (baseline 43 (10) pg/ml; 1 year 29 (7) (p = 0.015), but there was no change in IL6 levels (baseline 158 (41), 1 year 151 (48)). Both IFNgamma and IL6 levels were significantly reduced after methotrexate treatment. This observation was supported by in vitro experiments. The production of IFNgamma by PBL was inhibited by A77-1726, but IL6 production by PBM was not inhibited. CONCLUSION: The differential effect on IFNgamma and IL6 production supports the hypothesis that activated T cells are preferentially inhibited by leflunomide. An explanation may be either inhibition of uridine synthesis or effects on signal transduction pathways.     

Filtration leukocytapheresis therapy in the treatment of rheumatoid arthritis patients resistant to or failed with methotrexate

Filtration leukocytapheresis (LCP) is a treatment for abnormal autoimmune states, which removes responsible leukocytes from the peripheral blood. To examine the efficacy of LCP therapy in the treatment of rheumatoid arthritis (RA), nine patients were selected, who were either resistant to methotrexate, or failed with methotrexate due to drug ineffectiveness or adverse side effects. For these patients, LCP therapy was performed once a week for five weeks. After five LCP treatments, the patients were observed for 12 weeks, to test the efficacy of the treatment. The definition of improvement given by the American College of Rheumatology (ACR core set) was used for efficacy evaluation of LCP therapy. As the result, 77.8% of the patients showed an ACR 20% response and 44.4% of the patients showed an ACR 50% response. With improvement of joint symptoms, IL-6 was significantly decreased at 8 weeks and 12 weeks after the treatment. The expression of adhesion molecules CD11a, CD11b, and CD18 on granulocytes decreased directly after the LCP treatment. No adverse side effect was monitored during the study period. These results indicates that LCP treatment is a useful treatment for RA patients who were resistant to methotrexate, or failed with methotrexate due to ineffectiveness or side effects of the drug.     

Rheumatoid arthritis and osteoporosis

Summary Some controversial issues in the current literature in relation to osteoporosis and rheumatoid arthritis are updated and discussed.¶ Because most studies agree that osteoporosis in postmenopausal women and in men with RA is more evident at the hip and radius than at the spine, and that the most important determinants of bone loss are disability, local disease activity, and cumulative corticosteroid dose, osteoporosis is not a common systemic extra-articular manifestation of RA. In early arthritis, periarticular osteoporosis does indeed reflect disease activity because it is closely related to the acute phase reactants, but once periarticular osteoporosis is established it is no longer a marker of disease severity.¶ The threshold dose for corticosteroid-induced osteoporotic fractures is the cumulative rather than the actual dose. Statements based on quantitative tomography concerning the acute effects (and their reversal) of corticosteroids on bone have to be interpreted with care because of important body composition changes, in particular in bone marrow fat, during corticosteroid treatment. At present there is no evidence that anti-resorbing drugs can change the progress of RA erosions, probably because erosions are the result of non-osteoclast mediated mechanisms. Stress fractures in RA are underdiagnosed and are often confused with synovitis, and therefore it is likely that they are more frequent than commonly thought, especially in the lower limbs.¶ Methotrexate osteopathy is known in oncological practice. Whether low dose methotrexate is toxic for bone is not clear, but a number of clinical observations suggest that the occurrence of spontaneous fractures and lower extremity pain is more frequent in methotrexate treated patients than expected. Prospective studies are necessary to confirm these impressions.