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Paul Emery - One of the best experts on this subject based on the ideXlab platform.
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certolizumab pegol efficacy across Methotrexate regimens a pre specified analysis of two phase iii trials
Arthritis Care and Research, 2016Co-Authors: Bernard Combe, Desiree Van Der Heijde, Edward C Keystone, Lucian Ionescu, Daniel E Furst, Niti Goel, Kristel Luijtens, Paul EmeryAbstract:Objective. Anti-tumor necrosis factor agents (anti-TNFs) are frequently used in combination with Methotrexate to treat rheumatoid arthritis (RA). We investigated the effect of background Methotrexate dose, in combination with anti-TNF certolizumab pegol (CZP), on treatment efficacy and safety in RA patients. Methods. A pre-specified subgroup analysis comparing two Methotrexate dose categories ( 10 and ≤15 mg/week; and >15 mg/week. Results. 638, 635 and 325 patients received CZP 200 mg, CZP 400 mg and placebo, respectively. At Week 24, treatment responses in both CZP groups were uninfluenced by baseline Methotrexate dose category, and were superior to placebo group, for all investigated endpoints: ACR20/50/70, DAS28(ESR) and mTSS. TEAE incidence rates were higher in patients receiving Methotrexate ≥15 mg/week for most TEAE types, across treatment groups. Conclusion. CZP efficacy was not affected by background Methotrexate dose category. It can be hypothesized that to minimize TEAEs, background Methotrexate doses could
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sustained remission with etanercept tapering in early rheumatoid arthritis
The New England Journal of Medicine, 2014Co-Authors: Paul Emery, Bernard Combe, Mohammed Hammoudeh, Oliver Fitzgerald, E Martinmola, Maya H Buch, Marek Krogulec, Theresa Williams, Stefanie Gaylord, R PedersenAbstract:BACKGROUND We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-Methotrexate therapy. METHODS Patients with early active disease who had not previously received Methotrexate or biologic therapy received 50 mg of etanercept plus Methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus Methotrexate (combination-therapy group), Methotrexate alone, or placebo for 39 weeks (doubleblind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase. RESULTS Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the Methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P = 0.009 for combination therapy vs. Methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received Methotrexate alone, and 15 (23%) who had received placebo were in remission (P = 0.10 for combination therapy vs. Methotrexate alone; P = 0.02 for combination therapy vs. placebo; P = 0.55 for Methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the Methotrexate-alone group, and 2 (3%) in the placebo group. CONCLUSIONS In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-Methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to Methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.)
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radiographic changes in rheumatoid arthritis patients attaining different disease activity states with Methotrexate monotherapy and infliximab plus Methotrexate the impacts of remission and tumour necrosis factor blockade
Annals of the Rheumatic Diseases, 2009Co-Authors: Josef S Smolen, Paul Emery, Chenglong Han, D Van Der Heijde, Joan M Bathon, E Keystone, R N Maini, J R Kalden, Daniel Aletaha, Daniel BakerAbstract:Objective: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with Methotrexate with or without infliximab. Methods: Patients (n=1049) with active RA for ≤T3 years and no prior Methotrexate treatment were randomly assigned (4:5:5) to receive Methotrexate plus placebo or Methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Disease activity was classified by the simplified disease activity index (SDAI) score as remission (≤3.3), low (>3.3 to ≤T11), moderate (>11 to „T26), high (>26). Radiographic progression was measured as change from baseline to week 54 in total Sharp score (TSS). Results: At weeks 14 and 54, more patients receiving Methotrexate plus infliximab than Methotrexate plus placebo were in remission (10.7% vs. 2.8% week 14; 21.3% vs. 12.3% week 54; p Conclusion: With Methotrexate, joint damage progresses even at low and moderate disease activity levels, while Methotrexate plus infliximab inhibits radiographic progression across all disease activity states.
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infliximab chimeric anti tumour necrosis factor α monoclonal antibody versus placebo in rheumatoid arthritis patients receiving concomitant Methotrexate a randomised phase iii trial
The Lancet, 1999Co-Authors: R N Maini, Josef S Smolen, Daniel E Furst, Paul Emery, William E St Clair, Ferdinand C Breedveld, Joachim R Kalden, Michael H Weisman, Gregory Harriman, Marc FeldmannAbstract:Summary Background Not all patients with rheumatoid arthritis can tolerate or respond to Methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor α (TNF α) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving Methotrexate. Methods In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous Methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of Methotrexate (median 15 mg/week for ≥6 months, range 10–35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. Findings At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus Methotrexate (p vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus Methotrexate in the same treatment groups, compared with 5% of patients on placebo plus Methotrexate (p Interpretation During 30 weeks, treatment with infliximab plus Methotrexate was more efficacious than Methotrexate alone in patients with active rheumatoid arthritis not previously responding to Methotrexate.
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infliximab chimeric anti tumour necrosis factor alpha monoclonal antibody versus placebo in rheumatoid arthritis patients receiving concomitant Methotrexate a randomised phase iii trial attract study group
The Lancet, 1999Co-Authors: Ravinder N Maini, Josef S Smolen, Paul Emery, Ferdinand C Breedveld, Joachim R Kalden, Michael H Weisman, Gregory Harriman, E W St Clair, D E Furst, Marc FeldmannAbstract:Summary Background Not all patients with rheumatoid arthritis can tolerate or respond to Methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor α (TNF α) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving Methotrexate. Methods In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous Methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of Methotrexate (median 15 mg/week for ≥6 months, range 10–35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. Findings At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus Methotrexate (p vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus Methotrexate in the same treatment groups, compared with 5% of patients on placebo plus Methotrexate (p Interpretation During 30 weeks, treatment with infliximab plus Methotrexate was more efficacious than Methotrexate alone in patients with active rheumatoid arthritis not previously responding to Methotrexate.
Claire Bombardier - One of the best experts on this subject based on the ideXlab platform.
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Methotrexate monotherapy and Methotrexate combination therapy with traditional and biologic disease modifying anti rheumatic drugs for rheumatoid arthritis a network meta analysis
Cochrane Database of Systematic Reviews, 2016Co-Authors: Glen Hazlewood, Cheryl Barnabe, Deborah A. Marshall, George Tomlinson, Daniel J Devoe, Claire BombardierAbstract:Background Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining Methotrexate with other DMARDs. Objectives To compare Methotrexate and Methotrexate-based DMARD combinations for rheumatoid arthritis in patients naive to or with an inadequate response (IR) to Methotrexate. Methods We systematically identified all randomised controlled trials with Methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for Methotrexate-naive and Methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. Main results 158 trials with over 37,000 patients were included. Methotrexate-naive: Several treatment combinations with Methotrexate were statistically superior to oral Methotrexate for ACR50 response: Methotrexate + sulfasalazine + hydroxychloroquine (“triple therapy”), Methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for Methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral Methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral Methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than Methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to Methotrexate, several treatments were statistically significantly superior to oral Methotrexate for ACR50 response: triple therapy (moderate quality evidence), Methotrexate + hydroxychloroquine (low quality evidence), Methotrexate + leflunomide (moderate quality evidence), Methotrexate + intramuscular gold (very low quality evidence), Methotrexate + most biologics (moderate to high quality evidence), and Methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of Methotrexate + biologic DMARDs that were statistically significantly superior to oral Methotrexate. No treatment was statistically significantly superior to oral Methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and Methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral Methotrexate and Methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. Authors' conclusions We found moderate to high quality evidence that combination therapy with Methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or Methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in Methotrexate-naive patients or after an inadequate response to Methotrexate. Methotrexate + some biologic DMARDs were superior to Methotrexate in preventing joint damage in Methotrexate-naive patients, but the magnitude of these effects was small over one year.
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Methotrexate monotherapy and Methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis abridged cochrane systematic review and network meta analysis
BMJ, 2016Co-Authors: Glen Hazlewood, Cheryl Barnabe, Dan Devoe, Deborah A. Marshall, Claire Bombardier, George TomlinsonAbstract:Objective To compare Methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to Methotrexate. Design Systematic review and Bayesian random effects network meta-analysis of trials assessing Methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. Data sources Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. Study selection criteria Randomized or quasi-randomized trials that compared Methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. Main outcomes American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. Results 158 trials were included, with between 10 and 53 trials available for each outcome. In Methotrexate naive patients, several treatments were statistically superior to oral Methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine (“triple therapy”), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with Methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral Methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than Methotrexate plus infliximab. After an inadequate response to Methotrexate, several treatments were statistically superior to oral Methotrexate for ACR50 response: triple therapy, Methotrexate plus hydroxychloroquine, Methotrexate plus leflunomide, Methotrexate plus intramuscular gold, Methotrexate plus most biologics, and Methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral Methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. Conclusions Triple therapy (Methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with Methotrexate were effective in controlling disease activity, and all were generally well tolerated in both Methotrexate naive and Methotrexate exposed patients.
Josef S Smolen - One of the best experts on this subject based on the ideXlab platform.
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adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus Methotrexate or Methotrexate alone the randomised controlled optima trial
The Lancet, 2014Co-Authors: Josef S Smolen, Hartmut Kupper, Roy Fleischmann, Ronald F Van Vollenhoven, K Pavelka, Patrick Durez, Benoit Guerette, Laura ReddenAbstract:Summary Background Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus Methotrexate or Methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus Methotrexate or Methotrexate monotherapy. Methods This trial was done at 161 sites worldwide. Patients with early ( Findings The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus Methotrexate; 517 to placebo plus Methotrexate). 466 patients in the adalimumab plus Methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus Methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued Methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the Methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2–28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus Methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. Interpretation Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and Methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus Methotrexate achieved the low disease activity target compared with those initially treated with Methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus Methotrexate. Funding AbbVie.
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radiographic changes in rheumatoid arthritis patients attaining different disease activity states with Methotrexate monotherapy and infliximab plus Methotrexate the impacts of remission and tumour necrosis factor blockade
Annals of the Rheumatic Diseases, 2009Co-Authors: Josef S Smolen, Paul Emery, Chenglong Han, D Van Der Heijde, Joan M Bathon, E Keystone, R N Maini, J R Kalden, Daniel Aletaha, Daniel BakerAbstract:Objective: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with Methotrexate with or without infliximab. Methods: Patients (n=1049) with active RA for ≤T3 years and no prior Methotrexate treatment were randomly assigned (4:5:5) to receive Methotrexate plus placebo or Methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Disease activity was classified by the simplified disease activity index (SDAI) score as remission (≤3.3), low (>3.3 to ≤T11), moderate (>11 to „T26), high (>26). Radiographic progression was measured as change from baseline to week 54 in total Sharp score (TSS). Results: At weeks 14 and 54, more patients receiving Methotrexate plus infliximab than Methotrexate plus placebo were in remission (10.7% vs. 2.8% week 14; 21.3% vs. 12.3% week 54; p Conclusion: With Methotrexate, joint damage progresses even at low and moderate disease activity levels, while Methotrexate plus infliximab inhibits radiographic progression across all disease activity states.
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infliximab chimeric anti tumour necrosis factor α monoclonal antibody versus placebo in rheumatoid arthritis patients receiving concomitant Methotrexate a randomised phase iii trial
The Lancet, 1999Co-Authors: R N Maini, Josef S Smolen, Daniel E Furst, Paul Emery, William E St Clair, Ferdinand C Breedveld, Joachim R Kalden, Michael H Weisman, Gregory Harriman, Marc FeldmannAbstract:Summary Background Not all patients with rheumatoid arthritis can tolerate or respond to Methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor α (TNF α) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving Methotrexate. Methods In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous Methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of Methotrexate (median 15 mg/week for ≥6 months, range 10–35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. Findings At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus Methotrexate (p vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus Methotrexate in the same treatment groups, compared with 5% of patients on placebo plus Methotrexate (p Interpretation During 30 weeks, treatment with infliximab plus Methotrexate was more efficacious than Methotrexate alone in patients with active rheumatoid arthritis not previously responding to Methotrexate.
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infliximab chimeric anti tumour necrosis factor alpha monoclonal antibody versus placebo in rheumatoid arthritis patients receiving concomitant Methotrexate a randomised phase iii trial attract study group
The Lancet, 1999Co-Authors: Ravinder N Maini, Josef S Smolen, Paul Emery, Ferdinand C Breedveld, Joachim R Kalden, Michael H Weisman, Gregory Harriman, E W St Clair, D E Furst, Marc FeldmannAbstract:Summary Background Not all patients with rheumatoid arthritis can tolerate or respond to Methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor α (TNF α) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFα monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving Methotrexate. Methods In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous Methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of Methotrexate (median 15 mg/week for ≥6 months, range 10–35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. Findings At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus Methotrexate (p vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus Methotrexate in the same treatment groups, compared with 5% of patients on placebo plus Methotrexate (p Interpretation During 30 weeks, treatment with infliximab plus Methotrexate was more efficacious than Methotrexate alone in patients with active rheumatoid arthritis not previously responding to Methotrexate.
Martin P Zeidler - One of the best experts on this subject based on the ideXlab platform.
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Methotrexate is a jak stat pathway inhibitor
PLOS ONE, 2015Co-Authors: Sally Thomas, Katherine H Fisher, John A Snowden, Sarah Danson, Stephen Brown, Martin P ZeidlerAbstract:Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified Methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that Methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, Methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with Methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and Methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of Methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose Methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose Methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual Methotrexate cost of around £32, our findings represent an important development with significant future potential.
Fiorella Ilariucci - One of the best experts on this subject based on the ideXlab platform.
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high dose cytarabine plus high dose Methotrexate versus high dose Methotrexate alone in patients with primary cns lymphoma a randomised phase 2 trial
The Lancet, 2009Co-Authors: Andres Jose Maria Ferreri, Michele Reni, Marco Foppoli, Maurizio Frezzato, Maria Giuseppina Cabras, Alberto Fabbri, Maurizio Martelli, Gerassimos A. Pangalis, Gaetano Corazzelli, Fiorella IlariucciAbstract:Summary Background Chemotherapy with high-dose Methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose Methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to Methotrexate in patients with newly diagnosed primary CNS lymphoma. Methods This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18–75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either Methotrexate 3·5 g/m 2 on day 1 (n=40) or Methotrexate 3·5 g/m 2 on day 1 plus cytarabine 2 g/m 2 twice a day on days 2–3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314. Findings All randomly assigned participants were analysed. After chemotherapy, seven patients given Methotrexate and 18 given Methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6–30) and 46% (31–61), respectively, (p=0·006). Nine patients receiving Methotrexate and nine receiving Methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25–55) and 69% (55–83), respectively, (p=0·009). Grade 3–4 haematological toxicity was more common in the Methotrexate plus cytarabine group than in the Methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one). Interpretation In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose Methotrexate provides improved outcome with acceptable toxicity compared with high-dose Methotrexate alone. Funding Swiss Cancer League.
