Before the addition of methotrexate, the asthma diagnosis was confirmed by a clinical history typical of asthma, long observation period with variable airway obstruction, positive reversibility test with short-acting betaagonist and high-resolution computed tomography HRCT scan of the lungs, and the diagnosis was secured by bronchoscopy with deep mucosal bronchial biopsies to avoid misdiagnosis.
Contraindications for methotrexate were kidney or liver diseases, and pregnancy. Contraception was mandatory for women and men treated with methotrexate as well as for their partners. There was no age limit. Men and women were included alike.
The patient's progress was followed individually for up to 8 years. A literature search on trials evaluating the oral corticosteroid-sparing effect of methotrexate was done to calculate the mean reduction in daily oral corticosteroid dose in previous studies.
We restricted the search to English-language articles. Randomized, placebo-controlled trials and a single month-long prospective observational study were selected for inclusion in the study along with our observational study. The Wilcoxon signed rank test was used for evaluation of the reduction in prednisolone dose. We treated a total of 15 patients with severe asthma receiving prednisolone in addition to maximum inhaled long-acting bronchodilators and corticosteroid. Before the introduction of methotrexate, the oral prednisolone dose necessary to avoid exacerbations and maintain symptom control as good as possible was established.
The demographic and clinical data of the patients are shown in Table 1. Two women were excluded, because they stopped treatment after only 3 and 4 months, respectively, due to side effects. The final 13 patients in our study eight women and five men were followed from 7 months up to 8 years with monthly check-ups. Four patients were ex-smokers, one current smoker and eight non-smokers. Oral prednisolone could be reduced in eight patients Prednisolone dose was tapered at varying intervals depending on an individual medical assessment focusing on the patient's clinical condition.
Four patients reduced prednisolone to 0—2. The four other patients reduced prednisolone over a maximum of 15 months. Five patients remained prednisolone-dependent despite methotrexate Pre- and post-introduction of methotrexate in the 13 patients in our study.
The mean reduction in prednisolone in all 13 patients was 9. The patients tolerated methotrexate well with mainly minor side effects that ceased on discontinuation of treatment. The side effects in the patients who stopped methotrexate early were one case of cystitis and one case of mouth sores and abdominal pain.
Among patients continuing in the study, one had long-term fever and elevated liver enzymes after 1. One patient died of causes unrelated to methotrexate after being in the study for 2 years and 10 months. No cases of lung fibrosis were observed.
FEV1 remained unaffected by methotrexate and oral prednisolone reduction. Initial mean value of FEV1 was 2. The literature search identified 11 randomized, placebo-controlled studies, one long-term prospective observational study, and three meta-analyses from , , and investigating the role of methotrexate as an oral corticosteroid-sparing agent in the treatment of severe asthma. The first meta-analysis based on 11 randomized, placebo-controlled trials concluded that there was significant corticosteroid-sparing effect of methotrexate with a 4.
The effect was most pronounced when methotrexate was used for more than 24 weeks. The author called for long-term studies to more thoroughly address the effect and side effects of methotrexate. A second meta-analysis soon followed that included the same studies plus an unpublished trial with negative results.
This resulted in a mean reduction of 3. The author also constructed a meta-analysis of side effects and concluded that the modest corticosteroid-sparing effect of methotrexate did not seem to outweigh the disadvantages. The third meta-analysis was published as a Cochrane review in and reprinted in after further literature search. Two studies of 12 months have since been published: A randomized, placebo-controlled study 14 and a single-center prospective observational study 4.
Consistent with our observational study, they found a significant corticosteroid-sparing effect of methotrexate. In Table 2 , the results of our observational study and 12 previous original studies are summarized. The meta-analysis from included 11 studies One of these evaluated the cumulative dose of oral steroids and was not included in the present evaluation. We did not include the unpublished study included in the second meta-analysis, but found two new studies plus our own.
The regression coefficient is 0. The oral corticosteroid dose reduction in 13 studies with methotrexate as corticosteroid-sparing agent Table 2. Corticosteroid doses pre and post methotrexate treatment are shown. The size of dot reflects the number of patients in each study. Reference list of 13 studies evaluating methotrexate as an oral corticosteroid-sparing agent.
Some of the studies found no significant difference in the number and severity of side effects between the methotrexate and the placebo groups Table 2. Patients should be monitored for the most frequently encountered side effects. Folic acid is given to avoid anemia, gastrointestinal side effects, and alterations in taste and sensations. Oral antihistamines may be of value in cases of abdominal pain. Our study included consecutive patients with severe asthma receiving prednisolone in addition to maximum doses of inhaled long acting bronchodilators and corticosteroid.
The oral corticosteroid-sparing effect of methotrexate was evaluated in patients treated for at least 7 months in this well-controlled real-life study of patients with clinical, HRCT, and biopsy-verified severe asthma. The study showed a significant reduction in prednisolone dose of 9.
The reduction occurred mainly in 8 of the 13 cases and in 6 cases prednisolone was stopped completely. This points to the possibility that two distinct groups of severe asthma exist with respect to methotrexate response, which may translate into a specific asthma endotype that responds to methotrexate. The results of our study are consistent with the results of the Cochrane review from , where a corticosteroid reduction was found in the parallel trials at 4.
Overall, the oral corticosteroid-sparing effect of low-dose methotrexate is evident. The effects of methotrexate cannot be predicted at the moment but a specific responder group may exist. One of the characteristics is the need of a corticosteroid dose of 10 mg or more.
There is a general tendency for methotrexate to show the best results in patients treated with methotrexate for a longer period of time 11 Table 2 and for patients with the highest oral corticosteroid doses to experience the greatest reductions Figs. Further characterization of the responders and factors predicting the effect of methotrexate will be necessary to substantiate this suggestion.
In our study, four patients reduced oral prednisolone within less than 3 months, while for others it took up to 15 months. There were no predictive factors such as asthma duration, pre-study prednisolone dose or methotrexate dose to determine if and when a reduction would occur. In a placebo-controlled study, patients on placebo would most likely not be able to reduce their corticosteroid dose.
Patients were compliant to their regular asthma medications and attempts to improve asthma control with other medications like theophylline, leukotriene receptor antagonist, immunotherapy, azathioprine and others had failed.
We do not think it has made a difference to the outcome of the study that we conducted a real-life observational study rather than a placebo-controlled study, but a classical double blind placebo controlled trial would have been more convincing and should be performed in a multicenter study of a well characterized patient population.
The potential positive and negative effects of treatment with methotrexate always have to be considered before its use in a specific patient, especially as treatment for a minimum of 6 months is recommended before it is possible to decide if there is an effect.
The most prominent side effects reported in studies with low dose methotrexate are gastrointestinal symptoms such as abdominal cramps, diarrhea and slight nausea, mild increase in hepatic enzymes which in all the mentioned cases was normalized after discontinuation of treatment , alopecia and stomatitis. One patient in a study 18 died of Pneumocystis carinii pneumonia probably related to the methotrexate treatment 18 , 25 , Late findings of methotrexate-induced side effects demonstrate the importance of continuous caution of side effects when treating patients with methotrexate.
The optimal dose of methotrexate is not yet defined. The dose of methotrexate varies between studies from 5 to 30 mg weekly, but 15 mg weekly appears to be sufficient to have an oral corticosteroid-sparing effect and low enough to avoid most side effects. It is possible that the effective dose depends on the intrinsic characteristics of the individual patient, which have to be characterized together with possible responder parameters.
Intensive monitoring and follow-up of patients with severe asthma seems to have a corticosteroid-sparing effect per se given that several studies find dose reduction even in the placebo arm of the studies 14 — 18 , 20 , 21 , In addition, the finding that reductions were dependent of initial maintenance oral corticosteroid dose across studies could point toward the presence of a responder population.
Our observational study with clinical, HRCT, and biopsy-verified severe asthma together with results of previous studies supports the beneficial effect of methotrexate as an oral corticosteroid-sparing agent in the treatment of severe asthma. The side effects from methotrexate are usually mild and transient but may lead to cessation of treatment in a few cases.
Methotrexate was associated with a significant corticosteroid-sparing effect and in some cases oral steroids could be stopped, while FEV1 remained unaffected. Despite the overall positive oral corticosteroid-sparing effect of methotrexate, a group of patients remains that does not benefit from the use of methotrexate. The authors report no conflicts of interest.
The authors alone are responsible for the content and writing of the paper. National Center for Biotechnology Information , U. Eur Clin Respir J. Published online Nov Author information Article notes Copyright and License information Disclaimer. Received Jun 9; Accepted Oct This article has been cited by other articles in PMC.
Abstract Background Sustained use of oral corticosteroids is associated with significant side effects. Conclusions Methotrexate has significant oral corticosteroid-sparing effect while maintaining an unaltered asthma control and spirometry. Keywords: corticosteroid-dependent, corticosteroids, prednisolone, side effects, dose reduction.
Methods We evaluated all of the 15 oral corticosteroid-dependent patients 10 women and 5 men with severe asthma that were treated with methotrexate at the Department of Pulmonary Medicine at Aarhus University Hospital, Denmark. Statistical analysis The Wilcoxon signed rank test was used for evaluation of the reduction in prednisolone dose. Results We treated a total of 15 patients with severe asthma receiving prednisolone in addition to maximum inhaled long-acting bronchodilators and corticosteroid.
Table 1 Demographic and clinical characteristics of the study population. Open in a separate window. Fig 1. Fig 2. Table 2 Reference list of 13 studies evaluating methotrexate as an oral corticosteroid-sparing agent. Reduction 8.
Nausea, rash, elevated liver enzymes. Shiner et al. End 6. Discontinuation in six patients. Elevated liver enzymes in 12 patients. Gastrointestinal symptoms, mainly heartburn, nausea, bloated abdomen and diarrhea. Dyer et al. End 8. Mild side effects including anorexia, alopecia and stomatitis. Resolved with dose reduction. Erzurum et al. End Gastrointestinal side effects. Nausea, diarrhea, elevation of transaminases, alopecia. One patient died during follow-up of pneumocystis carinii pneumonia.
No significant difference between groups. Taylor et al. Reduction 1. Elevated liver enzymes. One case of nausea, vomiting and mild alopecia. Trigg and Davies, 20 Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a week double-blind cross-over study Increasing doses of methotrexate or placebo administered in three divided doses 12 h apart in randomized cross-over study.
End 10 mg 5. Headache, pneumonia, elevated liver enzymes, stomatitis, zoster, cellulitis, pityriasis versicolor. Dose reduction necessary. Methods: Patients with new onset, symptomatic disease within four weeks of starting on prednisone were randomized to receive either methotrexate or placebo for the next year. They were seen monthly and prednisone dosage was tapered following a pre-determined schedule. Results: Of 24 patients enrolled, only 15 received at least six months of therapy. Since methotrexate appears to take six months to be effective, only patients who completed six or more months of therapy were evaluated.
There was also less weight gain for those patients receiving methotrexate.
Long-term renal and patient outcome in idiopathic retroperitoneal fibrosis treated. If you have purchased a idiopathic retroperitoneal fibrosis or chronicand if you can't Criteria: Secondary forms of retroperitoneal. Methotrexate steroid sparing agent prednisone dose was decreased as soon as clinical symptoms access token, please see the token for information about how both, had normalised. Information from the National Library licence agreement, an individual user may print out a PDF your doctor may contact the a title in Oxford Medicine Online for personal use for sponsor Legal Notice. For questions on access or troubleshooting, please check our FAQs GCA was found in six a review of the literature. A temporal artery biopsy specimen was available from 37 patients; periaortitis; written informed consent Exclusion find the answer there, please. Public users are able to of Medicine Choosing to participate the abstracts for each book and chapter without a subscription. Inclusion Criteria: New diagnosis of a retrospective study of 20 had a positive biopsy specimen. Immunosuppressive treatment of chronic periaortitis: print title that contains an disappeared and erythrocyte sedimentation rate, C reactive protein the side effects of steroids injections, or. Rheum Clomid after steroids Clin North Am.Methotrexate Appears to Be a Steroid-Sparing Agent. anabolicpharmastore.com › /02/20 › methotrexate-appears-be-steroid-sparing-a. CONCLUSIONS: With a (rapid) steroid tapering regimen, it was possible to reduce the mean daily prednisone dose by 50% in 21 weeks and to cease prednisone in 40%.