Efficacy Of Low-dose Methotrexate Research Articles

Auxiliary in vitro and in vivo biological evaluation of hydrogen peroxide sensitive prodrugs of methotrexate and aminopterin for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes severe joints damage and other extra-articular alterations. Despite the efficacy of low-dose methotrexate (LD-MTX) in RA treatment, adverse effects are the predominant reasons for discontinuation of therapy. As a therapeutic targeting strategy, the presence of increased concentrations of reactive oxygen species (ROS) in the inflammatory environment can serve as the stimulus for prodrug activation in site-selective drug delivery systems. Our group has previously reported novel ROS sensitive prodrugs (1–3) of MTX and aminopterin (AMT) for site-selective delivery to inflammatory tissue associated with RA, with the aim of reducing side effects in RA therapy. Herein, we investigate the effect and toxicity of the same prodrugs in a rat CIA (collagen-induced arthritis) model of RA. We find that prodrug 1, an arylboronic acid ROS-sensitive MTX-prodrug, displays similar in vivo efficacy as MTX at an equimolar dose, while avoiding adverse effects known to restrict MTX treatment. To further characterize prodrug 1 and its ROS mediated activation, we synthesized compound 4, a negative control lacking the boronic acid moiety. We then investigated the effect of molecules on cell proliferation and cytotoxicity in the presence of the ROS scavenger pyruvate, as well as their stability in buffer and cell media, demonstrating a direct correlation between ROS concentration and the prodrug activity. Moreover, the in vitro ADME properties were investigated, including permeability, rat plasma and microsomal stability.

Evaluation of safety and efficacy of low-dose methotrexate as an alternative treatment option to systemic corticosteroids in generalized lichen planus

Introduction: Lichen planus (LP) is a common, chronic, inflammatory pruritic disorder involving the skin, mucous membranes, nails, and hair follicles. Systemic corticosteroids have long been treatment of choice for generalized LP. However, use of corticosteroids is limited due to multiple side effects. Methotrexate (MTX) can be used as alternative and safe modality in generalized LP. Materials and Methods: Twenty-two cases of generalized LP with comorbidities such as diabetes mellitus and hypertension and steroid-resistant and patients with side effects of long-term corticosteroids were included in this study. MTX was initiated at the dose of 7.5 mg/week. Clinical evaluation for improvement in lesions and pruritus was performed at 2nd, 4th, 8th, and 12th weeks. Results: After 12 weeks, 80% patients had excellent improvement. Patients with an excellent response were followed up. In the 6-month follow-up, four patients showed recurrence while all the remaining 12 showed complete remission. Conclusion: Results of this small study suggest that the use of weekly oral MTX can be highly effective and tolerable treatment alternative for generalized LP.

Chemotherapy for Generalized Infantile Myofibromatosis With Visceral Involvement

Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.

Safety and efficacy of low-dose methotrexate for pediatric patients with steroid-refractory acute graft-versus-host disease after hematopoietic stem cell transplantation

Low-dose methotrexate (LD-MTX) has long been included in prophylaxis regimens for acute graft-versus-host disease (aGVHD). In addition, LD-MTX is expected as a treatment option to control aGVHD by regulating the cytokine network. In this study, we retrospectively evaluated 35 patients with steroid-refractory acute GVHD to evaluate the safety and efficacy of LD-MTX as a salvage treatment. LD-MTX was administered weekly at a dose of 10 mg/m(2). Overall, 13 patients (37 %) achieved complete response and three (9 %) achieved partial response within 4 weeks after LD-MTX was initiated without any additional agents. Resolution of manifestations of aGVHD in each evaluable organ was observed in 12 of the 23 cases (52 %) with skin aGVHD and in eight of the 23 cases (35 %) with GI aGVHD. Neutropenia and thrombocytopenia (grades III and IV) were observed in nine (26 %) and 17 patients (49 %), respectively. Fatal infectious complications occurred in only three patients (9 %) after LD-MTX treatment. Of the 35 patients studied, 22 were alive with a median follow-up of 60 months and an overall survival rate (Kaplan-Meier estimate) was 62 %. LD-MTX seems suitable for salvage therapy and will not increase risk of infection. Further evaluation of the use of LD-MTX as salvage therapy for steroid-refractory acute GVHD is warranted.

Efficacy of low-dose methotrexate in the treatment of dermatomyositis skin lesions

A limited number of case series has indicated that methotrexate (MTX) might be a useful drug in the treatment of dermatomyositis (DM), a rare autoimmune disease involving the skin and muscles. However, these earlier studies mainly focused on the efficacy of MTX on DM muscular symptoms. To analyse the efficacy of MTX on skin lesions in DM, the records of 34 patients with DM seen between 2004 and 2009 were retrospectively analysed, and the DM skin disease activity at different time points was determined, with specific focus on cutaneous features using the validated Cutaneous Dermatomyositis Activity Index (CDASI) score. The lesional inflammation was scored in primary skin biopsies. Additionally, we performed a systematic review of the available literature. In our series, 11 patients with DM received MTX, and in 8 of them, MTX led to a significant reduction of the DM skin lesions. CDASI scores decreased from 15.7 to 6.4 (P < 0.01) within 2-3 months, supporting the effectiveness of MTX in skin disease in DM. The lymphocytic infiltrate in primary skin lesions of MTX responders was significantly more pronounced than that in nonresponders. These results indicate that MTX might be an effective drug to treat the cutaneous symptoms of DM, as measured by the validated CDASI. Interestingly, MTX responders histologically presented a significantly stronger lesional lymphocytic inflammatory infiltrate than did nonresponders. These findings suggest that the functional inhibition of lymphocyte migration in the skin might be an important mechanism of MTX in the treatment of DM.

Therapeutic efficacy of experimental rheumatoid arthritis with low-dose methotrexate by increasing partially CD4 +CD25 +Treg cells and inducing Th1 to Th2 shift in both cells and cytokines

Low-dose methotrexate (MTX), a traditional folate antagonist and disease-modifying antirheumatic drug administered weekly either alone or as combination therapy, is widely accepted as the gold standard in rheumatoid arthritis (RA) treatment. Although its mechanism of action in RA is still poorly understood, MTX potentially acts via antiproliferative, anti-inflammatory, and/or immunosuppressive means. The therapeutic mechanisms and efficacy of low-dose MTX and the oral tolerance protein natural chicken type II collagen (nCCII) were compared in vitro and in vivo using an established collagen-induced arthritis (CIA) rat model. We used clinical visual scoring, radiographic X-ray analysis, histopathological examination, and sera anti-CII IgG measurements to determine the severity of disease with and without treatment. Low-dose MTX had significant clinical therapeutic efficacy against established CIA. Similar to nCCII, MTX mediated CIA by specific immunotolerant effects and not by nonspecific immunosuppression. The mechanism underlying the therapeutic efficacy could be at least partially attributed to the increased production of CD4 +CD25 + Treg cells. These cells specifically downmodulated the T lymphocyte proliferative response to CCII but not PHA, induced a Th1-to-Th2 shift, downregulated Th1 cytokines, and upregulated both Th2 and Th3 cytokines. To the best of our knowledge, this is the first demonstration that low-dose MTX probably serves as a potent inducer of specific immunotolerance but not of nonspecific immunosuppression in the treatment of RA.

Safety and Potential Efficacy of Low Dose Methotrexate for Treatment of Chronic Graft-Versus-Host Disease.

Low dose methotrexate (MTX) is widely used for treatment of autoimmune diseases because of its anti-inflammatory activity. Encouraged by this practice, we have administered low dose MTX for treatment of refractory chronic GVHD, with the goal of reducing the amount of prednisone needed to control the disease. Fourteen patients with refractory chronic GVHD were treated with MTX at a dose of 7.5 mg/m2 per week for 3–50 weeks. All patients had involvement of the oral cavity and 11 of the 14 (78%) had skin involvement, often with scleroderma or fasciitis. The median duration of chronic GVHD at the start of MTX therapy was 38 (range 1–135) months. In this retrospective review, we found no grade 3–4 toxicities, and none of the patients required blood transfusion or treatment with hematopoietic growth factors. In 10 patients (71%), chronic GVHD could be adequately controlled with prednisone at doses below 1 mg/kg every other day without the addition of other immunosuppressive agents. Four patients decreased the amount of concomitant immunosuppressive treatment, 5 continued with the same regimen, 4 required an increase in immunosuppressive treatment, and one decided to discontinue all treatment. Improvement or resolution was observed most frequently in the gastrointestinal tract (80%) and skin (50%). From this preliminary analysis, MTX appears to be a well tolerated, inexpensive and possibly steroid-sparing immunosuppressive agent that is worthy of further evaluation in prospective trials for treatment of chronic GVHD.

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 2–4 mg every 12 h over a period of 24–36 h. Blood samples were taken 4 h 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 0.02 µM 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.

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 2-4 mg every 12 h over a period of 24-36 h. Blood samples were taken 4 h 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 0.02 microM 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.

Methotrexate use in rheumatoid arthritis. A clinician's perspective

Aminopterine, a precursor of methotrexate (MTX), was first used for the treatment of rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin. Am. J. Med. Sci. 221, 169–175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176–182.]. Corticosteroids, and to some extent cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s–early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as gold salts and d-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J. Rheumatol. 11, 760–763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489–496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 28, 721–730.]. Subsequently, these four trials were included in a meta-analysis and the drug was approved by the Food and Drug Administration for use in RA [Health and Public Policy Committee, H.P.P.C. and American College Physicians, A.C.P., 1987. Methotrexate in rheumatoid arthritis. Ann. Intern. Med. 107, 418–419; Paulus, H.E., 1986. FDA Arthritis Advisory Committee meeting: Methotrexate; guidelines for the clinical evaluation of antiinflammatory drugs; DMSO in scleroderma. Arthritis Rheum. 29, 1289–1290; Tugwell, P., Bennett, K., and Gent, M., 1987. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann. Intern. Med. 107, 358–366.]. Since then, rheumatologists have become aware of what Pincus et al. have called “the side effects” of RA comparing the morbidity and mortality caused by RA with that potentially caused by medications used to treat this disease [Pincus, T. and Callahan, L.F., 1993. The “side effects” of rheumatoid arthritis: joint destruction, disability and early mortality. Br. J. Rheumatol. 32, 28–37.]. Thus, during the 1990s the use of MTX for the treatment of RA became generalized [O'Dell, J.R., 1997. Methotrexate use in rheumatoid arthritis. Rheum. Dis. Clin. N Am. 23, 779–796 (a); Bannwarth, B., Vernhes, J., Schaeverbeke, T., and Dehais, J., 1995. The facts about methotrexate in rheumatoid arthritis. Rev. Rhum. 62, 471–473 (b); Bologna, C., Jorgensen, C., and Sany, J., 1997a. Methotrexate as the initial second-line disease modifying agent in the treatment of rheumatoid arthritis patients. Clin. Exp. Rheumatol. 15, 597–601; Bologna, C., Viu, P., Picot, M.C., Jorgensen, C., and Sany, J., 1997b. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate an open, retrospective, observational study. Br. J. Rheumatol. 36, 535–540.]. By now, basic and clinical investigators have gathered a wealth of information covering many aspects related to this compound, ranging from its mechanism of action to how it can be administered in a much safer way to patients.This article highlights the way in which MTX is currently used by rheumatologists for the treatment of RA primarily, and to a lesser extent for the treatment of other rheumatic disorders. Other aspects of this compound have been covered elsewhere and will not be emphasized in this review.

Methotrexate treatment for sarcoid-associated panuveitis

Objective To determine the safety and efficacy of low-dose methotrexate (MTX) for sarcoid-associated panuveitis. Design Retrospective noncomparative case series. Participants Twenty eyes from 11 patients were analyzed. Eight patients had sarcoidosis. Three patients were clinically suspected of sarcoidosis despite negative laboratory testing. All charts of patients with sarcoidosis and idiopathic uveitis seen by the Duke Uveitis Service from 1989 to 1997 were retrospectively reviewed. Those with sarcoid-associated or sarcoid-suspected panuveitis treated with MTX with a minimum of 6 months of follow-up were studied. Intervention Low-dose MTX was administered to patients weekly and patients were followed with serial ophthalmologic and medical examinations. Main outcome measures Visual acuity, oral and topical corticosteroid requirements, anterior chamber inflammation, and ability to undergo successful cataract extraction were used to measure the efficacy of MTX therapy. Results After MTX treatment was initiated, 90% of eyes had preserved or improved visual acuity. Mean initial Snellen visual acuity was 20/62 and mean final acuity was 20/40 ( P = 0.044). Of those patients initially requiring oral corticosteroids, the dosage was decreased in 100%, and they were completely discontinued in 86%. The mean initial oral corticosteroid dose was 26.6 mg and the mean final dose was 1.5 mg ( P = 0.012). Topical corticosteroids were decreased in 63% of eyes. The mean initial use was once every 1.6 hours, and the mean final use was once every 3.9 hours ( P = 0.001). Ninety-five percent of eyes had stabilized or decreased inflammation. The mean initial inflammation score was 1.2, and the mean final score was 0.5 ( P = 0.007). Five of six eyes previously unable to have cataract extraction because of uncontrolled inflammation became quiet on MTX and underwent surgery. One hundred percent of these eyes had improved vision after surgery. Side effects were mild and transient or reversible. Conclusion Low-dose MTX is an effective and safe adjunct to treat chronic sarcoid-associated panuveitis.

Methotrexate therapy in rheumatoid arthritis patients diminishes lectin-induced mononuclear cell proliferation

Methotrexate (MTX) is an anti-folate drug used in cancer chemotherapy because of its anti-proliferative effects. However, it is unclear whether the anti-proliferative effects of MTX contribute to the efficacy of low-dose MTX in the treatment of rheumatoid arthritis (RA). To date, either no change or a paradoxical increase in lectin-induced proliferation has been observed in cultures of peripheral blood mononuclear cells (PBMC) from MTX-treated RA patients (RA + MTX). In these earlier studies, high folate-containing media and tritiated thymidine (3H-TdR) were used. Our studies were designed to test the hypothesis that the use of a culture medium with a low folate content along with tritiated deoxyuridine (3H-UdR) permits detection of diminished phytohemagglutinin (PHA)-induced proliferative responses of PBMC from RA + MTX. The data demonstrate decreased PHA-induced cellular proliferation of cultured PBMC from RA + MTX compared with controls. When comparing the PBMC proliferative responses in high vs low folate medium, a significantly greater increase (P less than 0.05) in proliferation occurs in the cells from RA + MTX cultured in the high folate medium. This suggests that an in vivo folate-deficient state of the cells from RA + MTX may be corrected in vitro when a high folate medium is used in culture. We conclude that the use of 3H-UdR and a medium containing folate within the normal range of plasma folate levels eliminates artifacts associated with the use of high folate medium and 3H-TdR, which obscures the anti-proliferative effect of MTX in RA patients.