Browsing by Subject "METHOTREXATE"

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  • Eskelund, Christian W.; Kolstad, Arne; Jerkeman, Mats; Räty, Riikka; Laurell, Anna; Eloranta, Sandra; Smedby, Karin E.; Husby, Simon; Pedersen, Lone B.; Andersen, Niels S.; Eriksson, Mikael; Kimby, Eva; Bentzen, Hans; Kuittinen, Outi; Lauritzsen, Grete F.; Nilsson-Ehle, Herman; Ralfkiaer, Elisabeth; Ehinger, Mats; Sundstrom, Christer; Delabie, Jan; Karjalainen-Lindsberg, Marja-Liisa; Workman, Christopher T.; Garde, Christian; Elonen, Erkki; Brown, Peter; Gronbaek, Kirsten; Geisler, Christian H. (2016)
    In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.
  • Kuuliala, Krista; Kuuliala, Antti; Koivuniemi, Riitta; Kautiainen, Hannu; Repo, Heikki; Leirisalo-Repo, Marjatta (2017)
    Background: We found recently that baseline signal transducer and activator of transcription 3 phosphorylation in peripheral blood CD4(+) T cells of patients with early rheumatoid arthritis (RA) is associated with treatment response to synthetic disease-modifying antirheumatic drugs (DMARDs). This prompted us to study the baseline phosphorylation profiles of Janus kinases (JAKs) in blood leukocytes with respect to treatment response in early RA. Methods: Thirty-five DMARD-naive patients with early RA provided blood samples for whole blood flow cytometric determination of phosphorylation of JAKs in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Treatment response was determined after 1 year of treatment with synthetic DMARDs, with remission defined as absence of tender and swollen joints and normal erythrocyte sedimentation rate. Exact logistic regression was used to investigate the association of baseline variables with treatment response. Ninety-five percent CIs of means were estimated by bias-corrected bootstrapping. Results: High JAK3 phosphorylation in CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes and low JAK2 phosphorylation in CD14(+) monocytes were significantly associated with remission following treatment with synthetic DMARDs. Conclusions: Baseline JAK phosphorylation profile in peripheral blood leukocytes may provide a means to predict treatment response achieved by synthetic DMARDs among patients with early RA.
  • Gabay, Cem; Riek, Myriam; Hetland, Merete Lund; Hauge, Ellen-Margrethe; Pavelka, Karel; Tomsic, Matija; Canhao, Helena; Chatzidionysiou, Katerina; Lukina, Galina; Nordstrom, Dan C.; Lie, Elisabeth; Ancuta, Ioan; Victoria Hernandez, M.; van Riel, Piet L. M. C.; van Vollenhoven, Ronald; Kvien, Tore K. (2016)
    Objectives To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study. Methods Patients with rheumatoid arthritis treated with TCZ who had a baseline visit and information on concomitant sDMARDs were included. According to baseline data, patients were considered as taking TCZ as monotherapy or combination with sDMARDs. Main study outcomes were the change of Clinical Disease Activity Index (CDAI) and TCZ retention. The prescription of TCZ as monotherapy was analysed using logistic regression. CDAI change was analysed with a mixed-effects model for longitudinal data. TCZ retention was analysed with a stratified extended Cox model. Results Multiple-adjusted analysis suggests that prescription of TCZ as monotherapy varied according to age, corticosteroid use, country of the registry and year of treatment initiation. The change of disease activity assessed by CDAI as well as the likelihood to be in remission were not significantly different whether TCZ was used as monotherapy or in combination with sDMARDs in a covariate-adjusted analysis. Estimates for unadjusted median TCZ retention were 2.3 years (95% CI 1.8 to 2.7) for monotherapy and 3.7 years (lower 95% CI limit 3.1, upper limit not estimable) for combination therapies. In a covariate-adjusted analysis, TCZ retention was also reduced when used as monotherapy, with an increasing difference between mono and combination therapy over time after 1.5 years (p=0.002). Conclusions TCZ with or without concomitant sDMARDs resulted in comparable clinical response as assessed by CDAI change, but TCZ retention was shorter under monotherapy of TCZ.
  • Alberro, J. A.; Ballester, B.; Deulofeu, P.; Fabregas, R.; Fraile, M.; Gubern, J. M.; Janer, J.; Moral, A.; de Pablo, J. L.; Penalva, G.; Puig, P.; Ramos, M.; Rojo, R.; Santesteban, P.; Serra, C.; Sola, M.; Solarnau, L.; Solsona, J.; Veloso, E.; Vidal, S.; Abe, O.; Abe, R.; Enomoto, K.; Kikuchi, K.; Koyama, H.; Masuda, H.; Nomura, Y.; Ohashi, Y.; Sakai, K.; Sugimachi, K.; Toi, M.; Tominaga, T.; Uchino, J.; Yoshida, M.; Coles, C. E.; Haybittle, J. L.; Moebus, V.; Leonard, C. F.; Calais, G.; Garaud, P.; Collett, V.; Davies, C.; Delmestri, A.; Sayer, J.; Harvey, V. J.; Holdaway, I. M.; Kay, R. G.; Mason, B. H.; Blomqvist, C.; Saarto, T.; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG); GROCTA Trialists (2018)
    Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.
  • Färkkilä, Martti; Karvonen, Anna-Liisa; Nurmi, Heimo; Nuutinen, Hannu; Taavitsainen, Matti; Pikkarainen, Pekka; Kärkkäinen, Päivi (2004)
    No effective medical therapy is currently available for primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA) improves liver enzymes, but its effect on liver histology is controversial. Metronidazole (MTZ) prevents PSC-like liver damage in animal models and reduces intestinal permeability. We recruited 80 patients with PSC into a randomized placebo-controlled study to evaluate the effect of UDCA and MTZ (UDCA/MTZ) compared with UDCA/placebo on the progression of PSC. Patients (41 UDCA/placebo and 39 UDCA/ MTZ) were followed every third month. Assessment of liver function test, histological stage and grade, and cholangiography (via ERCP) at baseline showed no differences between the groups. After 36 months, serum aminotransferases gamma-glutamyltransferase, and alkaline phosphatase (ALP) decreased markedly in both groups, serum ALP more significantly in the UDCA/MTZ group (-337 +/- 54 U/L, P
  • Dammacco, Rosanna; Biswas, Jyotirmay; Kivelä, Tero T.; Zito, Francesco Alfredo; Leone, Patrizia; Mavilio, Alberto; Sisto, Dario; Alessio, Giovanni; Dammacco, Franco (2020)
    Purpose To describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed. Methods Data from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available. Results Ocular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Lofgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon's injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-alpha is a central mediator of granuloma formation, adalimumab, targeting TNF-alpha, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis. Conclusion Uveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.
  • Leppä, Sirpa; Jorgensen, Judit; Tierens, Anne; Meriranta, Leo; Østlie, Ingunn; Brown, Peter de Nully; Fagerli, Unn-Merete; Larsen, Thomas Stauffer; Mannisto, Susanna; Munksgaard, Lars; Maisenholder, Martin; Vasala, Kaija; Meyer, Peter; Jerkeman, Mats; Bjorkholm, Magnus; Fluge, Oystein; Jyrkklo, Sirkku; Liestol, Knut; Ralfkiaer, Elisabeth; Spetalen, Signe; Beiske, Klaus; Karjalainen-Lindsberg, Marja-Liisa; Holte, Harald (2020)
    Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P=.002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates.
  • Chatzidionysiou, K.; Lukina, G.; Gabay, C.; Hetland, M. L.; Hauge, E. M.; Pavelka, K.; Nordström, D.; Canhao, H.; Tomsic, M.; Rotar, Z.; Lie, E.; Kvien, T. K.; van Vollenhoven, R. F.; Saevarsdottir, S. (2019)
    Objectives: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). Method: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (Delta DAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. Results: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (Delta DAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). Conclusion: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.
  • Halonen, Sanna; Kankaanpää, Eeva; Kari, Juho; Parmanne, Pinja; Relas, Heikki; Kronstrom, Kai; Luosujärvi, Riitta; Peltomaa, Ritva (2017)
    Intra-articular glucocorticoid injections are the recommended treatment for active arthritis, but accurate positioning of the needle may be challenging. Inexperienced physicians might decide not to inject because an unsuccessful injection impairs clinical outcome and may lead to complications; however, choosing not to inject may impair or delay the best possible treatment. Here, we address this problem by introducing a novel Bioimpedance Probe (BIP) Needle-guidance method that was tested in a clinical study. The BIP Needle was utilized for detection of synovial fluid. It measures real-time bioimpedance spectra and identifies when the needle tip is in contact with the synovial fluid. Injections into 80 joints with active arthritis were performed by an experienced rheumatologist using the BIP Needle. The location of the BIP Needle was ensured by aspiration of synovial fluid, absence of resistance during injection, and/or using real-time ultrasound imaging. Sensitivity and specificity of the device for synovial fluid detection were 86 % (CI 75-93 %) and 85 % (CI 74-92 %), respectively. The BIP Needles showed high spatial resolution and differentiated the synovial fluid from the surrounding tissues. However, lack of synovial fluid, anatomic variability, and intra-articular structures challenged the technology. The BIP Needles provided adequate results in intra-articular injections. Performance of the device was good even in small joints, which may be the most difficult for inexperienced physicians. Further performance improvement can be expected when more data is collected for mathematical models. Overall, this novel method showed potential to be used in real-time needle guidance.
  • ReACCh-Out NoSPeR Investigators; Rypdal, Veronika (2019)
    Background: Models to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA. Methods: The Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction. Results: The Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83-0.87) for prediction of severe disease course and a C-index of 0.66 (0.63-0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80-0.89) and 0.69 (0.65-0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86-0.92). Conclusions: External validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course.