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.     

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.     

Anti-TNFalpha therapy for rheumatoid arthritis: an update

Many studies have confirmed that the long term use of biological agents targeting TNFalpha in therapy for rheumatoid arthritis give rise to sustained improvement in symptoms and signs of disease provided the anti-TNF agent is efficacious and of low immunogenicity. The current regimes for infliximab 3 or 10 mg/kg infusion in combination with weekly oral methotrexate, or of subcutaneous etanercept 25 mg twice per week fulfil these criteria. D2E7, a 'human' antibody produced by phage display, has also demonstrated efficacy in clinical trials. It has recently emerged that anti-TNF therapy protects joints from structural damage. One year data for infliximab and methotrexate combination therapy suggest that this regime reduces disability. In early RA, etanercept acts more rapidly than methotrexate to decrease symptoms and retard progression of erosions. In conclusion, for patients with established and early RA, anti-TNF therapies set a new standard for symptom control and joint protection.     

Noncardiogenic pulmonary edema in low-dose oral methotrexate therapy

In the past two decades, low-dose methotrexate (MTX) has been widely used in the treatment of rheumatoid arthritis (RA). As adverse effects, various types of pulmonary toxicity have been reported with this therapy. We report a case of MTX-induced noncardiogenic pulmonary edema in a 35-year-old woman. MTX used in high dose for anti-cancer therapy is known to cause non-cardiogenic pulmonary edema. However, there are no previous reports of noncardiogenic pulmonary edema caused by low-dose MTX therapy. This report suggests that patients receiving oral weekly, low-dose MTX may be at risk for the development of noncardiogenic pulmonary edema.     

Pulmonary lymphoma developed during long-term methotrexate therapy for psoriasis

Low dose weekly administration of methotrexate has been thought to be effective for both rheumatoid arthritis (RA) and psoriasis. However, there is a possibility that methotrexate therapy may be oncogenic. This report presents a case of pulmonary lymphoma developed during long-term methotrexate therapy for psoriasis. Physicians should be aware that Epstein-Barr virus-associated lymphoproliferative disorders that occur during treatment with methotrexate are not specific to patients with RA.     

Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group

CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA). OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA. DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study. SETTING: Forty-seven university and private rheumatology practices in the United States and Canada. PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment. INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk). MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population. RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy. CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.     

Early rheumatoid arthritis in a patient with Sjögren's syndrome and pulmonary nodular amyloidosis: clinical implication of early limited use of infliximab

Abstract

Infliximab, an anti-tumor necrosis factor α antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6^Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin κ light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200^Smg per infusion) and MTX (6^Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.     

Anti-tumor necrosis factor therapies

Recently published studies confirm that the long-term use of biologicals targeting tumor necrosis factor-alpha (TNF-alpha) in therapy for rheumatoid arthritis (RA) gives rise to sustained improvement in symptoms and signs of disease provided the anti-TNF agent is efficacious and of low immunogenicity. The current regimens for infliximab 3 or 10 mg/kg infusion in combination with weekly oral methotrexate, or of etanercept 25 mg subcutaneously twice per week, appear to fulfill these criteria. D2E7, a "human" antibody produced by phage display, has also been used for over a year. It has recently emerged that anti-TNF therapy protects joints from structural damage. The 1-year data for infliximab and methotrexate combination therapy suggest that this regimen reduces disability. In early RA, etanercept acts more rapidly than methotrexate to decrease symptoms and retard the progression of erosions. In conclusion, for patients with established and early RA, anti-TNF therapies set a new standard for symptom control and joint protection.     

Early rheumatoid arthritis in a patient with Sjögren's syndrome and pulmonary nodular amyloidosis: clinical implication of early limited use of infliximab

Infliximab, an anti-tumor necrosis factor α antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6^Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin κ light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200^Smg per infusion) and MTX (6^Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.     

Life threatening acute pneumonitis during low dose methotrexate treatment for rheumatoid arthritis: a case report and review of the literature.

A patient is described with definite rheumatoid arthritis (RA) who developed life threatening acute pneumonitis after receiving a total dose of only 12.5 mg methotrexate (MTX). This complication has been previously described, but this is probably the lowest reported dose before development of pneumonitis in a patient with RA. The possible significance of this case is discussed in the light of recent reports suggesting an increased susceptibility of patients with RA to the pulmonary toxicity of MTX.     

Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis

OBJECTIVE: The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) is a 3-year, double-blind, multicenter study evaluating the efficacy and safety of etanercept, methotrexate, and the combination of etanercept plus methotrexate in patients with active rheumatoid arthritis (RA). The results after 1 and 2 years of the study have been previously reported. Here we provide the 3-year clinical and radiographic outcomes and safety of etanercept, methotrexate, and the combination in patients with RA. METHODS: In this randomized, double-blind, multicenter TEMPO study, 682 patients received etanercept 25 mg twice weekly, methotrexate < or =20 mg weekly, or the combination. Key efficacy assessments included the Disease Activity Score (DAS) and the DAS in 28 joints. RESULTS: Combination therapy resulted in significantly greater improvement in the DAS and in more patients with disease in remission than either monotherapy. This finding was confirmed by longitudinal analysis; patients receiving combination therapy were more than twice as likely to have disease in remission than those receiving either monotherapy. Independent predictors of remission included male sex, lower disease activity, lower level of joint destruction, and/or better physical function. Combination and etanercept therapy both resulted in significantly less radiographic progression than did methotrexate (P < 0.05). Etanercept and combination treatment were well tolerated, with no new safety findings. CONCLUSION: Etanercept plus methotrexate showed sustained efficacy through 3 years and remained more effective than either monotherapy, even after adjustment for patient withdrawal. Combination therapy for 3 years led to disease remission and inhibition of radiographic progression, 2 key goals for treatment of patients with RA.     

Development of sarcoidosis 6-month post discontinuation of etanercept: coincidence or real association?

There have been numerous reports of granulomatous diseases developing in patients receiving anti-tumour necrosis factor (TNF) therapy. Herein, we report a patient who developed sarcoidosis 6?months after discontinuation of etanercept. To date, all reported cases have occurred in patients undergoing ongoing treatment with TNF blockers with resolution on its discontinuation. A 47-year-old man was diagnosed with seropositive rheumatoid arthritis (RA) in 2003. He was initially treated with methotrexate and corticosteroids. In 2005, adalimumab was added due to ongoing disease activity. However, he had persistent low-grade synovitis of bilateral wrist joints and remained oral glucocorticoids dependent. In October 2008, adalimumab was switched to etanercept with marginal benefit; however, etanercept was continued until March 2009. Rituximab was discontinued due to an immediate allergic reaction. In September 2009, he developed bilateral ankle synovitis with erythema nodosum. Further investigations (chest X-ray and CT scan of thorax) revealed new development of bilateral hilar lymphadenopathy and interstitial nodular changes typical of sarcoidosis. His baseline therapy of methotrexate was continued. His recent repeat chest X-ray and CT scan of thorax (March 2010) has shown significant spontaneous resolution of his mediastinal lymphadenopathy and pulmonary nodules. Apart from the initial brief course of NSAIDs, his sarcoidosis resolved spontaneously without requiring any further therapy. For his rheumatoid arthritis, he has been recently commenced on abatacept and his baseline therapy of methotrexate has been continued. It remains speculative as to whether the concurrence of RA and sarcoidosis is purely serendipitous, or is related to an immunodysregulatory state attributable to TNF blockade.     

Etanercept (Enbrel): update on therapeutic use

Tumour necrosis factor (TNF) is an important inflammatory disease mediator in a wide spectrum of articular diseases, including adult and juvenile rheumatoid arthritis (RA, JRA). Etanercept (Enbrel), approved in the United States and in Europe for use in patients with RA and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both of these diseases. Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time. To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate, and to examine the effect of etanercept on radiographic progression, a double blind, placebo controlled study was recently conducted, comparing etanercept with methotrexate (median dose 20 mg per week). Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA, and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions. In patients with severe psoriatic arthritis (PsA), a double blind, placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA. Etanercept has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases.     

Effect of etanercept on fatigue in patients with recent or established rheumatoid arthritis

OBJECTIVE: To assess the long-term impact of etanercept on fatigue in patients with recent-onset (mean duration 11 months) or established (mean duration 12 years) rheumatoid arthritis (RA). METHODS: Patients participating in either of 2 multicenter, randomized, double-blind clinical trials were included. In one trial, patients with recent-onset RA received either etanercept 25 mg twice weekly or methotrexate in a double-blind fashion for 12 months, then open label for 12 months. All patients then received open-label etanercept. In the second trial, patients with established RA received etanercept 25 mg or placebo twice weekly for 6 months in a double-blinded fashion, then open-label etanercept. Up to 46 months of followup data were included. Fatigue was measured regularly using the Health Assessment Questionnaire vitality domain. RESULTS: Patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months. Subsequently, patients receiving etanercept and methotrexate had 23-29% and 17-24% reductions in fatigue scores, respectively. In the group with established RA, patients who received etanercept had significantly greater reductions in fatigue than those receiving placebo during the blinded period. Patients initially receiving etanercept sustained a mean fatigue reduction of 25-36% for the entire followup. Patients achieving clinically meaningful improvement in fatigue were more likely to meet the American College of Rheumatology improvement criteria. CONCLUSION: Etanercept therapy reduces fatigue in patients with recent-onset or established RA. Improvement in fatigue was sustained for up to 46 months, and correlated with other RA-relevant outcomes.     

The in vivo effect of nonsteroidal anti-inflammatory drugs, gold sodium thiomalate and methotrexate on neutrophil superoxide radical generation

The generation of superoxide radicals by activated peripheral blood polymorphonuclear leukocytes from patients with rheumatoid arthritis (RA) has been measured and the in vivo effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease remittive agents studied. Generation of superoxide radicals from RA patients was significantly decreased when compared to a control population. This was principally due to the disease rather than medications in that patients with osteoarthritis receiving NSAID generated superoxide radicals similar to that seen in the control group. RA patients receiving NSAIDs and injectable gold or methotrexate therapy showed a significant trend to normalization of superoxide radical generation when compared to those with RA receiving NSAIDs alone. We conclude that the reduced generation of superoxide radicals on activated polymorphonuclear leukocytes from patients with RA is principally a feature of the disease and that this abnormality can be partially reversed by the use of a disease remittive agent in vivo.     

Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis

We describe 5 patients with rheumatoid arthritis (RA) who developed pulmonary complications following infliximab therapy; 4 patients had preexisting usual interstitial pneumonia. As the pathophysiology of the pulmonary insult is unknown, we advise caution in the use of anti-tumor necrosis factor-alpha therapy in patients with RA with underlying lung disease of sufficient severity to withhold methotrexate treatment.     

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)     

Long‐term treatment with methotrexate or tumor necrosis factor α 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 α (TNFα) 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 TNFα inhibitors in patients with RA does not significantly influence EBV load in PBMCs.     

Cryptococcosis associated with low-dose methotrexate for arthritis

One patient with psoriatic arthritis and a second with rheumatoid arthritis were each treated with low-dose methotrexate (10 to 15 mg per week, orally) for more than a year before pulmonary cryptococcosis developed. These are the first case reports of opportunistic fungal disease during this treatment. Low-dose methotrexate may be more immunosuppressive than has been appreciated. Patients demonstrating pneumonitis while receiving this therapy should be carefully evaluated to rule out an infectious cause.     

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.