Low-dose Oral Methotrexate Research Articles

'Idiopathic' Eosinophilia with an Occult T-Cell Clone: Prevalence, FIP1L1-PDGFRA Status, and Clinical Course.

Background: Blood eosinophilia results either from autonomous expansion of a myeloid stem/progenitor cell, or as a response to cytokines that promote growth and differentiation of eosinophil progenitors. A subset of patients with hypereosinophilic syndrome/idiopathic eosinophilia (HES/IE) display abnormal T-cell immunophenotype and/or clonal rearrangements of the T-cell receptor (TCR), operationally assigned the term “lymphocyte variant” HES/IE. Information on the prevalence, FIP1L1-PDGFRA status, and clinical course of such patients is limited.Methods: Consecutive patients with eosinophilia were identified by querying our institutional electronic database from 1995 to 2004. Clonal rearrangements of the γchain of the TCR were identified by polymerase chain reaction followed by gel electrophoresis in all cases, and confirmed by Southern Blot analysis of the gene coding for the β chain of the TCR, using standard methods. FIP1L1-PDGFRA was screened by fluorescence in situ hybridization.Results: We studied a total of 205 consecutive patients with eosinophilia defined as an absolute eosinophil count (AEC) of > 600/μL, who also had a bone marrow study performed. Of these, TCR gene rearrangements studies were performed in 99 patients (AEC range of 650 to 38,000/μL) including 3 children and 96 adults (age range 18 to 88 years; 58 males). Among these 99 patients, 14 (~14%) had a demonstrable T-cell clone in peripheral blood, bone marrow aspirate, lymph node, and/or skin. Six of the 14 patients with a demonstrable T-cell clone were found to have a concurrent T-cell malignancy at the time of evaluation including T-cell large granular lymphocytic (T-LGL) leukemia - 1 case and peripheral T-cell lymphoma - 5 cases. The other 8 (~8%) patients otherwise fulfilled the working diagnosis of “lymphocyte variant” HES/IE (median AEC=2045/μL, range 720/μL to 9600/μL). The median duration of eosinophilic prodrome, prior to identification of the occult T-cell clone was 5 years (range 3 months to 11 years), and virtually all had dominant skin involvement presenting as dermatitis (5 cases) or episodic angioedema with eosinophilia (EAE) (2 cases). Five of 7 patients tested had an elevated serum IgE level, and a similar proportion displayed an abnormal T-cell immunophenotype (most commonly, aberrant CD5 and/or CD7 expression). Six of the 8 patients with an occult T-cell clone were evaluated for FIP1L1-PDGFRA and tested negative. Two patients were effectively treated with low-dose oral cyclophosphamide or methotrexate (follow-up duration of 3+ and 6+ years, respectively) whereas imatinib treatment was ineffective in another 2 patients. Two patients (25%) transformed into cutaneous T-cell lymphoma after 3 to 8 years of eosinophilic prodrome.Conclusion: The current study suggests that the presence of a T-cell clone in idiopathic eosinophilia is a marker/harbinger of a primarily skin-based peripheral T-cell lymphoma that responds to T cell-directed therapy but not imatinib therapy, which is consistent with the absence of FIP1L1-PDGFRA in such cases.

‘Idiopathic’ eosinophilia with an Occult T-cell clone: Prevalence and clinical course

In a study of 99 consecutive patients with ‘idiopathic’ eosinophilia, clonal T-cells were demonstrated in blood, bone marrow, or other tissue samples of 14 patients including 6 who had an overt T-cell malignancy. The remaining eight patients (∼8%) with an ‘Occult’ T-cell clone had predominantly cutaneous disease and FIP1L1- PDGFRA was absent in all six evaluable patients. Two patients were effectively treated with low-dose oral cyclophosphamide or methotrexate whereas Gleevec ® treatment was ineffective in another two patients. Two patients (25%) transformed into cutaneous T-cell lymphoma after 3–8 years of eosinophilic prodrome.

T‐cell large granular lymphocyte leukemia

To the authors' knowledge, there is no standard treatment for patients with T-cell large granular lymphocyte (LGL) leukemia. Available data are limited by patient numbers and coexisting pathologies. The authors report on the use of immunosuppressants (cyclosporin A [CSA] and low-dose oral methotrexate [MTX] given continuously) and cytotoxic agents in the treatment of 29 patients with T-cell LGL leukemia age over the past 20 years. The overall response rate (ORR) to MTX (n = 8 patients) was 85.7% (complete hematologic response [CHR] rate, 14.3%; partial response [PR] rate, 71.4%) with dose-dependent responses observed and safe usage of doses >10 mg/m2 per week in 2 patients. The ORR to CSA (n = 23 patients) was 78.2% (CHR rate, 30.4%; PR rate, 47.8%). The median time to response for both agents was 1 month. Toxicity, although it was minor in most patients and was more common in the CSA group, included second malignancies in 5 patients. An ORR of 67% (all CHR) was attained with pentostatin (n = 4 patients); recurrences developed after a median of 4.6 years. Successful retreatment with pentostatin was possible but with increasing drug resistance. Cyclophosphamide induced CHR that lasted >7 years with bone marrow clearance in 1 of 4 patients. Alemtuzumab induced a PR in 1 patient who had refractory disease. Both MTX and CSA were efficacious in the treatment of T-cell LGL leukemia but generally required long-term maintenance therapy. The authors highlight the risks of second malignancies and persistence of bone marrow disease. Although MTX and CSA were effective as first-line therapy, alemtuzumab and pentostatin merit further investigation, particularly for refractory disease.

Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects

Background: We previously demonstrated efficacy and impact on serum vascular endothelial growth factor (VEGF) for metronomic cyclophosphamide (C) and methotrexate (M) in patients with breast cancer. New metronomic schedules were investigated.Patients and methods: Patients with advanced breast cancer were randomized to receive oral C (50mg daily) and M (2.5mg twice daily on days 1 and 4) (arm A) or the same regimen plus thalidomide (200mg daily) (arm B).Results: The mean VEGF level decreased from 378.9 (± 274.4) pg/ml at baseline to 305.9 (± 203.6) pg/ml at 2 months (P < 0.001), with similar change with respect to baseline in both arms. In 171 evaluable patients we observed three complete remissions (CR) in both arms A and B, 15 partial remission (PR) in arm A and seven in arm B, for an overall response of 20.9% [95% confidence interval (CI) 12.9% to 31%] in arm A and 11.8% (95% CI 5.8% to 20.6%) in arm B. The clinical benefit (CR + PR + SD ≥ 24 weeks) was 41.5% for both arms. Toxicity was generally mild. Higher neurological toxicity (2% versus 60%; P < 0.0001) and constipation (8% versus 51%; P < 0.0001) was observed in arm B.Conclusions: Metronomic low-dose CM induced a drop in VEGF, and was effective and minimally toxic. The addition of thalidomide did not improve results.

Low-Dose Oral Methotrexate for Maintaining Crohn??s Disease Remission

Methotrexate has been considered a second-line immunomodulating therapy, behind azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP), for the treatment of Crohn's disease (CD). Approximately 27% to 50% of patients with refractory CD are intolerant or resistant to AZA or 6-MP. Two well-designed randomized double-blind placebo-controlled trials have demonstrated that low-dose methotrexate (<25 mg/wk), given intramuscularly (IM), is effective in inducing and maintaining remission in CD. In clinical practice, IM injection involves an inconvenience for patients and higher costs. Furthermore, frequent IM injections increase the risk of complications such as peripheral nerve injury, local irritation, pain, bleeding, fibrosis, abscess formation, gangrene, and contractures. Alternatively, subcutaneous (SQ) injection has been advocated because it has been shown to have similar pharmacokinetics to IM injection. However, because of a recent and ongoing national shortage of parenteral methotrexate, patients who were receiving IM methotrexate had to switch to the oral form until the parenteral formulation becomes available. Oral methotrexate has been used with great success in treatment of rheumatoid arthritis and psoriasis for the past 50 years. However, the data on the usage of low-dose oral methotrexate in maintaining CD remission are scanty and controversial. The purpose of this article is to review the mechanism of action, absorption, and the objective evidence in supporting the use of oral methotrexate in maintaining CD remission.

Low-dose methotrexate treatment for oligoarticular juvenile idiopathic arthritis nonresponsive to intra-articular corticosteroids

The objective of this study was to evaluate the efficacy of low-dose (0.2 mg/kg) methotrexate (MTX) in the treatment of children with oligoarticular juvenile idiopathic arthritis (JIA) who do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and repeated intra-articular corticosteroid (IA) injections. Nineteen consecutive patients (age: 2-14 years, 18 females) with oligoarticular JIA were studied prospectively. Sixteen had a persistent course and three had an extended course of the disease. Patients were defined as nonresponders to IA injections if the duration of improvement following two consecutive injections was less than 4 weeks. These patients were offered low-dose oral MTX, administered once a week for at least 6 months. Of the 19 patients in this series, 2 responded to NSAIDs alone. Forty-eight IA injections were given to 17 patients; 11 (64%) of them did not respond to this treatment. Nine of the nonresponders were treated with low-dose MTX for a median duration of 15+/-3.8 months. Except for one patient with an extended disease course, all responded very well to treatment and went into remission after a median of 6.4+/-2.9 months, and none required additional IA injections after initiation of MTX treatment. Low-dose oral MTX appears to be very effective in the management of children with oligoarticular JIA, who are unresponsive to IA injections.

Response Time and Safety Profile of Pulsed Oral Methotrexate Therapy in Idiopathic Retinal Periphlebitis

To evaluate the response time and safety profile of low-dose oral methotrexate pulsed therapy in idiopathic retinal periphlebitis (Eales' disease). A tertiary care center-based prospective interventional study, based on visual acuity grading, was undertaken. Twenty-one consecutive patients with idiopathic retinal periphlebitis were administered 12.5 mg methotrexate as a single oral dose, once per week for 12 weeks (cumulative dose = 150 mg). Each patient was assessed for change in visual acuity grades. Time of first therapeutic response was also noted. Drug safety was monitored by laboratory tests that included twice-weekly white blood cells and differential counts, twice-weekly platelet counts, and monthly liver function tests. Twenty-one eyes were assessed. Mean follow-up period was 6 months. All showed improvement in visual acuity grades. An excellent visual outcome (6/6 or better) was achieved in 18 (69%) eyes. Time of first therapeutic response varied from 2 to 6 weeks with a majority of eyes (80%) showing response by 4 weeks (median = 3 weeks). All the side effects of methotrexate were mild or moderate in severity and rapidly reversible on dose reduction or discontinuation. No patient had any constitutional symptoms severe enough to necessitate cessation of therapy. Low dose oral methotrexate pulse therapy (at a dose of 12.5 mg/week) is clinically effective within 4 weeks, and is associated with an acceptable safety profile.

Lessons from a case of T-cell large granular lymphocytic leukaemia suggesting that immunomodulatory therapy is more effective than intensive treatment

Leukemia treatment strives to eradicate the malignant clone. With T-cell large granular lymphocytic (LGL) leukemia, the onus of treatment appears to be modification of the disease rather than eradication of the clone. We describe a case of T-cell LGL leukemia where aggressive, eradicative type therapy proved ineffective. The patient achieved hematological response to low dose oral methotrexate after failing to respond to and/or tolerate eight previous treatments including CAMPATH-1H and peripheral blood stem cell transplantation. We highlight the resistant nature of the LGL clone and discuss the relative merits of immunomodulatory type therapy in this disease.

Methotrexate therapy for ocular cicatricial pemphigoid

Purpose To report the use of methotrexate therapy as first-line systemic therapy in the treatment of ocular-cicatricial pemphigoid and drug-induced ocular-cicatricial pemphigoid. Design Retrospective, noncomparative, interventional case series. Participants Twelve patients with ocular-cicatricial pemphigoid and 5 patients with drug-induced ocular-cicatricial pemphigoid treated with low-dose oral methotrexate as the sole systemic agent. In 14 of the 17 patients, methotrexate was the first systemic agent used. Methods Clinical data abstracted from patient medical records. Main outcome measures Visual acuity, conjunctival inflammation, progression of cicatrization, and treatment-related side effects. Results After a mean follow-up duration of 30.2 months (range, 6–78 months), complete control or suppression, or both, of conjunctival inflammation was achieved in 89% of eyes with ocular-cicatricial pemphigoid and in 100% of eyes with drug-induced ocular-cicatricial pemphigoid using methotrexate monotherapy as the first-line systemic agent. Progression of conjunctival cicatrization was prevented in 72% of eyes with ocular-cicatricial pemphigoid and 90% of eyes with drug-induced ocular-cicatricial pemphigoid. Visual acuity was maintained or improved in 85% of total eyes treated with methotrexate monotherapy, and a final visual acuity of 6/18 or better was achieved in 74% of the eyes. Methotrexate therapy was well tolerated, with 92% of patients maintained on continued treatment experiencing no side effects. The most common side effects were gastrointestinal (50%), and most (78%) were reversible on dose reduction. In 4 of 17 cases, methotrexate was ceased as a result of possible treatment-related side effects. Conclusions Low-dose oral methotrexate monotherapy is both highly efficacious and well tolerated as the first-line systemic agent in the treatment of ocular-cicatricial pemphigoid and drug-induced ocular-cicatricial pemphigoid.

Altered tissue expression pattern of cell adhesion molecules, ICAM-1, E-selectin and VCAM-1, in bullous pemphigoid during methotrexate therapy.

Little is known about how eosinophils accumulate in bullous pemphigoid (BP) and why these cells rapidly disappear during immunosuppressive therapy. Eosinophils can produce cytokines such as IL-4, IL-5, IL-6, IL-10 and IL13, which can induce endothelial cells to express cellular adhesion molecules (CAMs) such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) necessary for the recruitment of eosinophils from the bloodstream to the skin. The present aim was to investigate the cellular expression of these three CAMs in serial biopsies before and during oral low-dose methotrexate therapy. Seventy-four biopsy specimens, 37 from active lesions and 37 from normal skin, were taken at different intervals from eight patients with bullous pemphigoid and stained immunohistochemically with specific monoclonal antibodies for these three CAMs. The expression and distribution of CAMs in the biopsies was evaluated and scored with light-microscopic examination. The basal keratinocytes in active lesions expressed ICAM-1. A strong VCAM-1 expression of endothelial cells and pericytes was correlated to a perivascular inflammatory cell infiltrate that also showed intense immunoreactivity to ICAM-1. Endothelial cell/pericytes also expressed E-selectin strongly in the BP patients before therapy. The expression of CAMs faded during therapy and, to the best of our knowledge, this has not been previously reported. Thus we suggest that the rapid reduction of tissue eosinophils may reflect the altered pattern of cell adhesion molecules during immunosuppressive therapy, which could explain the prompt clinical improvement seen in BP patients treated with methotrexate.

A Case of Clinical Indolent Natural Killer Cell Lineage Large Granular Lymphocytic Leukemia in a Patient with Rheumatoid Arthritis

We report a case of natural killer (NK) cell leukemia with unusual biological features in a 65-year-old woman with a 20-year history of rheumatoid arthritis. She presented with neutropenia, thrombocytopenia, splenomegaly and bone marrow infiltration. Immunophenotyping (CD2+ CD3- CD4- CD5- CD8- CD16+ CD56-) confirmed NK cell leukemia. Her neutropenia and thrombocytopenia resolved following splenectomy and she has remained well with stable disease for 12 months on oral low-dose methotrexate. In contrast to all previous reports, in this instance the phenotype of large granular lymphocytic (LGL) leukemia occurring in the context of rheumatoid arthritis was NK-cell rather than T-cell. Furthermore, the clinical course was indolent, whereas, all prior literature reports have described a very aggressive clinical course for this disorder with a median survival of just 3.5 months. This case illustrates previously unrecognized heterogeneity in the natural history of this disorder.

Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels

BackgroundAnticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including cyclophosphamide (CTX), methotrexate (MTX), anthracyclines and taxanes, postulating an antiangiogenic activity. Patients and methodsWe evaluated the clinical efficacy and impact on serum vascular endothelial growth factor (VEGF) levels of low-dose oral MTX and CTX in patients with metastatic breast cancer. MTX was administered 2.5 mg bd on days 1 and 2 each week and CTX 50 mg/day administered continuously. ResultsSixty-four patients were enrolled, 63 were evaluable: Eastern Cooperative Oncology Group (ECOG) performance status 0–1, ≥2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and ≥2 regimens (n = 20). Among the 63 evaluable patients, there were two complete remissions (CR), 10 partial remissions (PR) for an overall response rate of 19.0% (95% CI 10.2% to 30.9%) and an overall clinical benefit (CR+ PR+ stable disease >24 weeks) of 31.7% (95% CI 20.6% to 44.7%). Grade ≥2 leucopenia was registered in only 13 patients. The median serum VEGF level for the subgroup of patients on treatment for at least 2 months decreased with treatment from 315 pg/ml (95% CI 245 to 435) at baseline to 248 pg/ml(95% CI 205 to 311) at 2 months (P <0.001). Both responders and non-responders showed similar reductions in serum VEGF (P = 0.78). After 6 months patients still on treatment had a median VEGF level of 195 pg/ml (95% CI 96 to 355), which was significantly lower than the median baseline values (P = 0.001). ConclusionsContinuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect.

Severe Pancytopenia Associated with Low-Dose Methotrexate Therapy for Rheumatoid Arthritis

OBJECTIVE:To report the occurrence of severe pancytopenia associated with low-dose methotrexate (MTX) therapy for rheumatoid arthritis.CASE SUMMARY:Two patients developed severe pancytopenia after 10 days (cumulative dose 15 mg) and 23 months (cumulative dose 1030 mg), respectively, of low-dose MTX therapy for rheumatoid arthritis. Both patients had renal impairment. One died and the other recovered completely.DISCUSSION:Pancytopenia is a rare adverse effect of low-dose oral MTX therapy. The exact mechanism for development of pancytopenia is unknown, although it is likely that several factors play a role. The most important risk factor for MTX toxicity is impaired renal function. This adverse effect may occur at any time during MTX therapy.CONCLUSIONS:Severe pancytopenia associated with low-dose MTX therapy for rheumatoid arthritis is a potentially serious complication that may occur at any time during therapy. This adverse effect is more likely to occur in patients with renal impairment.

Use of methotrexate in the management of sight-threatening uveitis

Managing chronic inflammatory immune-mediated eye diseases currently involves the non-specific suppression of the immune system. Oral corticosteroids are still the chief component of this therapy, but additional immunosuppressive agents are often indicated to control the disease as well as to avoid the side effects of long-term therapy with high doses of corticosteroids. Many different drugs are available including cyclosporine, azathioprine and occasionally cyclophosphamide, chlorambucil, or more recently mycophenolate mofetil and tacrolimus (FK-506). Pulsed low-dose oral methotrexate (MTX) is now widely used in rheumatological disease and has been introduced in the management of sight-threatening uveitis. Some reports using low doses advocate its use as an alternative when multiple drug therapy is necessary or to help lower the dose of other drugs. In our group of 11 patients with long-standing disease, adding MTX to the treatment regimen allowed control of the inflammation with a reduction of the corticosteroid dose in more than 50% of the cases and decreased the number of disease relapses in 45%. These results indicate that MTX is useful as an alternative option when a second/third agent is needed, achieving a better control of the disease in some cases.

Circulating levels of soluble E-selectin, ICAM-1 and VCAM-1 in bullous pemphigoid during low-dose methotrexate therapy. A prospective study.

Soluble iso-forms of cellular adhesion molecules (sCAMs) have been described and reported to be elevated in various inflammatory diseases. Elevated levels of sE-selectin have recently been detected and found to correlate with the number of blisters in bullous pemphigoid (BP) during oral corticosteroid therapy. In this prospective study we analysed levels of sCAMs in 10 elderly BP patients during low-dose oral pulse methotrexate monotherapy. We used standardised ELISA kits for soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin on 65 sera from 10 patients and 19 controls. Results were correlated with clinical parameters. Before therapy, we found significant elevation of sE-selectin (P=0.004) and sVCAM-1 (P=0.002) but not of sICAM-1. sE-selectin levels decreased during the efficient therapy and correlated with the number of blisters. Our results further support the proposition that sE-selectin might be a future clinical and predictive tool; but whether the elevation of sVCAM-1 also might reflect the disease activity in BP needs more investigation. The findings also indicate that BP might be more a cellularly mediated disease where interactions of different adhesion molecules play a crucial role.

Interventions for psoriatic arthritis.

To assess the effects of salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. We searched Medline up to 1995, and Excerpta Medica (June 1974-95). Search terms were psoriasis, arthritis, therapy and/or controlled trial. This was supplemented by manually searching bibliographies of previously published reviews, conference proceedings and contacting drug companies. All languages were included in the initial search. All randomized trials comparing salazopyrin, auranofin, etretinate, fumaric acid, IMI gold, azathioprine, and methotrexate, in psoriatic arthritis. The main outcome measures included individual component variables derived from Outcome Measures in Rheumatology Clinical Trials (OMERACT). These include Acute Phase Reactants, Disability, Pain, Patient Global Assessment, Physician Global Assessment, Swollen joint count, Tender joint count and radiographic changes of joints in any trial of 1 year or longer [Tugwell 1993], and the change in pooled disease index. Only English trials were included in the review. Data were independently extracted from the published reports by two of the reviewers. An independent blinded quality assessment was also performed. Nineteen randomized trials were identified of which eleven were included in the quantitative analysis with data from 777 subjects. Although all agents were better than placebo, parenteral high dose methotrexate (not included), salazopyrin, azathioprine and etretinate were the agents that achieved statistical significance in a global index of disease activity (although it should be noted that only one component variable was available for azathioprine and only one trial was available for etretinate suggesting some caution is necessary in interpreting these results). Analysis of response in individual disease activity markers was more variable with considerable differences between different medications and responses. In all trials the placebo group improved over baseline (pooled improvement 0.43 DI units, 95% CI 0. 28-0.59). There was insufficient data to examine toxicity. Parenteral high dose methotrexate and salazopyrin are the only two agents with well demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with azathioprine, etretinate, oral low dose methotrexate and perhaps colchicine suggests that they may be effective but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition.

Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia.

Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia.

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.

Low-dose Oral Methotrexate Management of Patients with Bilateral Ménière's Disease

In this retrospective clinical trial, we evaluated the effectiveness of low-dose oral methotrexate in the management of bilateral Ménière's disease of immune-mediated origin. At our tertiary-care referral center, we evaluated ten men and eight women who had longstanding bilateral Ménière's disease that had been unresponsive to traditional conservative medical management. Sixteen of these patients had steroid-responsive bilateral Ménière's disease. Two patients had contraindications to steroids, but their clinical and laboratory evaluations were consistent with an immune-mediated process. Patients were treated with 7.5 to 20 mg/week of oral methotrexate. The mean duration of treatment was 16.7 months (range: 8 to 35), with a mean followup of 2 years (range: 9 mo to 5 yr). Changes in clinical symptoms (vertigo, hearing loss, tinnitus, and aural fullness), audiometric changes, and side effects of therapy were evaluated. Vertigo resolved in 14 patients (78%), was substantially alleviated in three patients (17%), and remained unchanged in one patient (6%). Hearing improved in five patients (28%) and stabilized in seven patients (39%). Tinnitus and aural fullness resolved or was relieved in 11 of 17 (65%) and 13 of 14 (93%) patients, respectively. Side effects were minimal and reversible. We conclude that low-dose oral methotrexate is effective and safe for treating bilateral Ménière's disease of immune-mediated origin. In this study, methotrexate alleviated vertiginous symptoms and improved or stabilized hearing in most patients. Low-dose methotrexate can be considered for patients with immune-mediated bilateral Ménière's disease when long-term treatment is required or when a steroid or cyclophosphamide is contraindicated.

Oral methotrexate in the management of refractory interstitial cystitis.

To establish the safety and efficacy of low-dose oral methotrexate in treating refractory interstitial cystitis, 9 women who fulfilled internationally accepted criteria for the diagnosis of interstitial cystitis were enrolled in a prospective study. All had proven unresponsive to conventional treatment modalities. Assessment by pain score and frequency volume charts was performed pretreatment and up to 6 months during therapy. No significant adverse side effects were noted. At the end of follow-up, 4 women had noted a subjective improvement in bladder pain and wished to continue on methotrexate, 4 women noted little change and 1 woman reported a worsening of symptoms. Overall there was a significant reduction in pain score (p = 0.047) posttreatment. However, there was no significant difference in urinary frequency per 24 hours (p = 0.40), maximum voided volume (p = 0.089) or mean voided volume (p = 0.59). Methotrexate significantly improved bladder pain in women with interstitial cystitis, although no significant change was found in voiding pattern.