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1.
Rheumatol Int ; 40(11): 1741-1751, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32880032

RESUMO

Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.


Assuntos
Antirreumáticos/uso terapêutico , Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Hidroxicloroquina/uso terapêutico , Metotrexato/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Colchicina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Metotrexato/efeitos adversos , Pandemias
2.
PLoS One ; 15(7): e0235637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628710

RESUMO

BACKGROUND: The high risk of cardiovascular disease is well recognized in rheumatoid arthritis. Type 2 diabetes also attributes to this increase in risk. Rheumatoid arthritis is a chronic inflammatory condition, which aggravates insulin resistance, placing the patients at a higher risk of type 2 diabetes and subsequent cardiovascular outcomes. Methotrexate treatment, as a gold standard anti-inflammatory drug in the treatment of rheumatoid arthritis has shown beneficial effects on cardiovascular health. However, its impact on type 2 diabetes is still unknown. OBJECTIVE: To assess the strength of the association between exposure to methotrexate and the rate of development of type 2 diabetes in rheumatoid arthritis patients. METHODS: All rheumatoid arthritis studies reporting the use of methotrexate as an exposure and type 2 diabetes as an outcome were searched until March 2020 using MEDLINE, Cochrane and Scopus databases. Studies were included if the diagnosis of rheumatoid arthritis was made according to current guidelines or by a rheumatologist, and if there was information about methotrexate exposure and the type 2 diabetes outcome. The author and an independent assessor evaluated the articles for eligibility. Meta-analyses combined relative risk estimates from each study where raw counts were available. RESULTS: Sixteen studies reporting sufficient data for inclusion in the meta-analyses were identified. Methotrexate showed a promising effect on the risk of type 2 diabetes as this risk decreased in rheumatoid arthritis patients using methotrexate (Relative risk 0.48, 95% CI 0.16, 1.43). CONCLUSION: Rheumatoid arthritis patients on methotrexate treatment had a lower risk of developing type 2 diabetes compared to rheumatoid arthritis patients not exposed to methotrexate. This finding highlights the need for future, randomized control trials to confirm the beneficial effect of methotrexate on type 2 diabetes in the rheumatoid arthritis population.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Metotrexato/uso terapêutico , Fatores Etários , Antirreumáticos/efeitos adversos , Artrite Reumatoide/patologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Metotrexato/efeitos adversos , Risco , Índice de Gravidade de Doença
3.
Cochrane Database Syst Rev ; 7: CD011174, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609376

RESUMO

BACKGROUND: Non-tubal ectopic pregnancy is the implantation of an embryo at a site lying outside the uterine cavity or fallopian tubes. Sites include a caesarean scar, the cornua uteri, the ovary, the cervix, and the abdomen. There has been an increasing trend in the occurrence of these rare conditions, especially caesarean scar pregnancy (CSP). OBJECTIVES: To evaluate the clinical effectiveness and safety of surgery, medical treatment, and expectant management of non-tubal ectopic pregnancy in terms of fertility outcomes and complications. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) search portal and nine other databases to 12 December 2019. We handsearched reference lists of articles retrieved and contacted experts in the field to obtain additional data. SELECTION CRITERIA: We included randomized controlled trials (RCTs) published in all languages that examined the effects and safety of surgery, medical treatment, and expectant management of non-tubal ectopic pregnancy. DATA COLLECTION AND ANALYSIS: We used Cochrane standard methodological procedures. Primary outcomes were treatment success and complications. MAIN RESULTS: We included five RCTs with 303 women, all reporting Caesarean scar pregnancy. Two compared uterine arterial embolization (UAE) or uterine arterial chemoembolization (UACE) plus methotrexate (MTX) versus systemic MTX and subsequent dilation and suction curettage; one compared UACE plus MTX versus ultrasonography-guided local MTX injection; and two compared suction curettage under hysteroscopy versus suction curettage under ultrasonography after UAE/UACE. The quality of evidence ranged from moderate to very low. The main limitations were imprecision (small sample sizes and very wide confidence intervals (CI) for most analyses), multiple comparisons with a small number of trials, and insufficient data available to assess heterogeneity. UAE/UACE versus systemic MTX prior to suction curettage Two studies reported this comparison. One compared UAE with systemic MTX and one compared UACE plus MTX versus systemic MTX, in both cases followed by a suction curettage. We are uncertain whether UAE/UACE improved success rates after initial treatment (UAE: risk ratio (RR) 1.00, 95% CI 0.90 to 1.12; 1 RCT, 72 women; low-quality evidence; UACE: RR 0.87, 95% CI 0.54 to 1.38; 1 RCT, 28 women; low-quality evidence). We are uncertain whether UAE/UACE reduced rates of complications (UAE: RR 0.47, 95% CI 0.13 to 1.75; 1 RCT, 72 women; low-quality evidence; UACE: RR 0.62, 95% CI 0.26 to 1.48; 1 RCT, 28 women; low-quality evidence). We are uncertain whether UAE/UACE reduced adverse effects (UAE: RR 1.58, 95% CI 0.41 to 6.11; 1 RCT, 72 women; low-quality evidence; UACE: RR 1.16, 95% CI 0.32 to 4.24; 1 RCT, 28 women; low-quality evidence), and it was not obvious that the types of events had similar values to participants (e.g. fever versus vomiting). Blood loss was lower in UAE/UACE groups than systemic MTX groups (UAE: mean difference (MD) -378.70 mL, 95% CI -401.43 to -355.97; 1 RCT, 72 women; moderate-quality evidence; UACE: MD -879.00 mL, 95% CI -1135.23 to -622.77; 1 RCT, 28 women; moderate-quality evidence). Data were not available on time to normalize ß-human chorionic gonadotropin (ß-hCG). UACE plus MTX versus ultrasonography-guided local MTX injection We are uncertain whether UACE improved success rates after initial treatment (RR 0.95, 95% CI 0.56 to 1.60; 1 RCT, 45 women; very low-quality evidence). Adverse effects: the study reported the same number of failed treatments in each arm (RR 0.88, 95% CI 0.40 to 1.92; 1 RCT, 45 women). We are uncertain whether UACE shortened the time to normalize ß-hCG (MD 1.50 days, 95% CI -3.16 to 6.16; 1 RCT, 45 women; very low-quality evidence). Data were not available for complications. Suction curettage under hysteroscopy versus under ultrasonography after UAE/UACE. Two studies reported this comparison. One compared suction curettage under hysteroscopy versus under ultrasonography after UAE, and one compared these interventions after UACE. We are uncertain whether suction curettage under hysteroscopy improved success rates after initial treatment (UAE: RR 0.91, 95% CI 0.81 to 1.03; 1 RCT, 66 women; very low-quality evidence; UACE: RR 1.02, 95% CI 0.96 to 1.09; 1 RCT, 92 women; low-quality evidence). We are uncertain whether suction curettage under hysteroscopy reduced rates of complications (UAE: RR 4.00, 95% CI 0.47 to 33.91; 1 RCT, 66 women; very low-quality evidence; UACE: RR 0.18, 95% CI 0.01 to 3.72; 1 RCT, 92 women; low-quality evidence). We are uncertain whether suction curettage under hysteroscopy reduced adverse effects (UAE: RR 3.09, 95% CI 0.12 to 78.70; 1 RCT, 66 women; very low-quality evidence; UACE: not estimable; 1 RCT, 92 women; very low-quality evidence). We are uncertain whether suction curettage under hysteroscopy shortened the time to normalize ß-hCG (UAE: MD 4.03 days, 95% CI -1.79 to 9.85; 1 RCT, 66 women; very low-quality evidence; UACE: MD 0.84 days, 95% CI -1.90 to 3.58; 1 RCT, 92 women; low-quality evidence). Non-tubal ectopic pregnancy other than CSP No studies reported on non-tubal ectopic pregnancies in locations other than on a caesarean scar. AUTHORS' CONCLUSIONS: For Caesarean scar pregnancies (CSP) it is uncertain whether there is a difference in success rates, complications, or adverse events between UAE/UACE and administration of systemic MTX before suction curettage (low-quality evidence). Blood loss was lower if suction curettage is conducted after UAE/UACE than after administration of systemic MTX (moderate-quality evidence). It is uncertain whether there is a difference in treatment success rates, complications, adverse effects or time to normalize ß-hCG between suction curettage under hysteroscopy and under ultrasonography (very low-quality evidence). There are no studies of non-tubal ectopic pregnancy other than CSP and RCTs for these types of pregnancy are unlikely.


Assuntos
Gravidez Ectópica/terapia , Abortivos não Esteroides/administração & dosagem , Abortivos não Esteroides/efeitos adversos , Viés , Cesárea , Quimioembolização Terapêutica/efeitos adversos , Cicatriz/complicações , Intervalos de Confiança , Dilatação e Curetagem/efeitos adversos , Dilatação e Curetagem/métodos , Feminino , Humanos , Histeroscopia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamanho da Amostra , Ultrassonografia de Intervenção , Artéria Uterina , Embolização da Artéria Uterina/efeitos adversos , Curetagem a Vácuo
4.
Medicine (Baltimore) ; 99(27): e20824, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629668

RESUMO

INTRODUCTION: Glucocorticoids (GCs), especially low-dose GCs, are commonly prescribed for rheumatoid arthritis (RA), although the risk/benefit ratio is controversial. A randomized, double-blind clinical trial was performed to evaluate the efficacy and safety of low-dose oral GCs combined with methotrexate (MTX) and hydroxychloroquine (HCQ) in early RA (ERA). METHODS: Eighty untreated ERA patients were randomized into the trial (GCs + MTX + HCQ) and control (placebo + MTX + HCQ) groups, for 1-year treatment. Therapeutic evaluation indices were American College of Rheumatology (ACR) 20 of ACR, disease activity score (DAS) 28- erythrocyte sedimentation rate (ESR), visual analog scale scores, joint function, health assessment questionnaire-disability index score, morning stiffness duration, C-reaction protein and ESR. The clinical indicators were evaluated pre-treatment and at 1st, 3th, 6th and 12th month of treatment. The MRI data of single joint (ie, the most swollen joint) for each patient were acquired with a revised OMERACT RAMRIS Scoring System before and after treatment. The correlation analysis was adopted to confirm whether the efficacy of GC treatment is related to the time of RA onset. The side effects (eg, gastrointestinal reactions, liver dysfunction, upper respiratory tract infection, leukocyte reduction) were also monitored. RESULTS: At 1st month, 55% and 20% cases in the experimental and control groups achieved ACR20 response, respectively, indicating a significant difference (χ = 16.157, P < .001). This trend continued until 6th month. At 12th month, the number of patients achieved ACR20 response was similar in both groups. At 1st to 6th month, DAS28- ESR scores in the experimental group were significantly lower than control values (all p < .05). The experimental group showed improved inflammation, quality of life and radiological symptoms. Bone erosion remained unchanged in the experimental group, while worsening in control group. Correlation coefficients between RA duration and DAS28-ESR score were 0.496, 0.464, 0.509, and 0.550 at 1st, 3th, 6th, and 12th month, respectively. No differences were found in adverse events between the 2 groups. CONCLUSIONS: Low-dose GCs combined with MTX and HCQ significantly achieves disease remission indexed by ACR20 and DAS28-ESR, and improves clinical and radiological outcomes in ERA patients at the early stage, with superiority over placebo + MTX + HCQ, without enhancing adverse reactions.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hidroxicloroquina/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Sedimentação Sanguínea , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença
5.
Anticancer Res ; 40(7): 3883-3888, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620628

RESUMO

BACKGROUND/AIM: The insulin-like growth factor type 1 receptor (IGF-1R) is overexpressed in myelodysplastic syndrome (MDS) cells, and 765IGF-Methotrexate (IGF-MTX) is a conjugate of methotrexate and a variant of insulin-like growth factor-1 (IGF-1) designed to selectively target cancer cells through binding to IGF-1R. The aim of this study was to determine whether IGF-MTX would be effective to treat MDS. PATIENTS AND METHODS: In this phase I clinical trial, two patients with high grade MDS or oligoblastic acute myeloid leukemia (O-AML) that had failed standard therapy were treated with IGF-MTX. RESULTS: No dose-limiting toxicity was observed. Both patients had stable or improved cell counts and CD34+ myelodysplastic cell counts and exceeded their life expectancy (both alive at 1.9 years despite a life expectancy of less than 6 months). Bone marrow blast counts decreased from 22% to 5% in one patient, and from 17% to 16% in the other. CONCLUSION: In conclusion, IGF-MTX at 0.20 µM equivalents per kg was well tolerated, caused no cytopenia, and produced stable disease and extension of life.


Assuntos
Imunoconjugados/administração & dosagem , Metotrexato/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/imunologia , Masculino , Metotrexato/efeitos adversos , Terapia de Alvo Molecular , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Gradação de Tumores , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/imunologia
6.
Pediatr Blood Cancer ; 67(7): e28387, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32400952

RESUMO

BACKGROUND: The standard practice during high-dose methotrexate (HD-MTX) in acute lymphoblastic leukemia (ALL) to mitigate toxicity is to serially monitor levels till serum MTX < 0.01 µmol/L. Most resource-limited centers lack in-house access to MTX levels, and therefore repeated monitoring is costly and cumbersome. We studied the efficacy and safety of "solitary 36 hours post HD-MTX levels (MTX36 )." PROCEDURE: This prospective observational study consecutively enrolled children with ALL receiving HD-MTX. Cycles with unavailable MTX36 and MTX36  > 10 µmol/L were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. MTX36 were performed at other centers. Leucovorin was given in six hourly doses 36 hours post HD-MTX. Hydration was continued until the last dose of leucovorin. MTX toxicities, including change of creatinine from baseline at 36 hours (∆Cr36 ), were noted. Two groups depending on MTX36 (≤1 µmol/L vs > 1 µmol/L) received six versus eight doses of leucovorin, and toxicities were compared. RESULTS: Twenty-nine children with median age five years (1-11) who received 100 HD-MTX cycles with a median MTX dose of 3 g/m2 (2-5) were analyzed. The median MTX36 level was 1.165 µmol/L (0.1-7.32). Toxicities of HD-MTX (CTCAE-4.0): transaminitis-22%; creatinine elevation ≥ 1.25 times baseline-24%; cytopenias-16%; mucositis-17%; acute kidney injury (AKI)-6%. All toxicities were ≤CTCAE grade 3. Creatinine elevation, AKI, and mucositis were significantly higher in the group with higher MTX36 . There was no correlation (r = 0.3) between ∆Cr36 and MTX36 . MTX36 was thrice more economical than the standard protocol. CONCLUSION: MTX36 is a potential cost-effective, efficacious, and safe limited sample strategy to monitor HD-MTX, particularly in centers where in-house MTX levels are unavailable.


Assuntos
Antimetabólitos Antineoplásicos/economia , Análise Custo-Benefício , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/economia , Metotrexato/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras/economia , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Criança , Pré-Escolar , Países em Desenvolvimento , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Metotrexato/efeitos adversos , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Estudos Prospectivos
7.
Int J Clin Pharmacol Ther ; 58(6): 293-298, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32301699

RESUMO

OBJECTIVES: We assessed the relative efficacy and safety of once-daily administration of 100 and 200 mg filgotinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: We conducted a Bayesian network meta-analysis combining the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of filgotinib in patients with active RA. RESULTS: Five RCTs involving 3,920 patients met the inclusion criteria. There were 15 pairwise comparisons, including 8 direct comparisons and 7 interventions. The ACR20 response rate was significantly higher in the filgotinib 200 mg + methotrexate (MTX) group than in the placebo or placebo + MTX group (odds ratio (OR): 12.39, 95% credible interval (CrI): 3.36 - 45.98.10; OR: 2.68, 95% CrI: 1.80 - 4.39). Compared to the placebo group, the filgotinib 100 mg, adalimumab 40 mg + MTX, filgotinib 200 mg, and placebo + MTX groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated filgotinib 200 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.902), followed by filgotinib 100 mg + MTX (SUCRA = 0.694), filgotinib 100 mg (SUCRA = 0.675), adalimumab 40 mg + MTX (SUCRA = 0.661), filgotinib 200 mg (SUCRA = 0.305), placebo + MTX (SUCRA = 0.259), and placebo (SUCRA = 0.005). The safety based on the number of serious adverse events (SAEs) did not differ significantly among 6 six interventions. CONCLUSION: Filgotinib 100 and 200 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk of SAEs.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Antirreumáticos/efeitos adversos , Teorema de Bayes , Quimioterapia Combinada , Humanos , Janus Quinase 1/antagonistas & inibidores , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metanálise em Rede , Piridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triazóis/efeitos adversos
8.
Clin Exp Rheumatol ; 38(5): 1008-1015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301430

RESUMO

OBJECTIVES: This systematic literature review (SLR) and network meta-analysis (NMA) was aimed at comparing the relative efficacy and safety of abatacept (ABA) with other currently recommended therapies for patients with early RA. METHODS: An SLR (January 1998 to June 2018) was conducted including MEDLINE®, Embase, and CENTRAL databases, and grey literature. Population was adults with active RA for ≤2 years treated with biologic DMARDs as monotherapy or in combination with conventional DMARDs. A Bayesian NMA was performed using randomised controlled trials (RCTs) and comparisons for ACR50, DAS28 remission, withdrawal due to adverse events and total withdrawal where reported. RESULTS: Ninety publications pertaining to 69 studies (43 RCTs and 26 observational studies) were identified. Twenty-eight RCTs were eligible to be included in the NMA. ABA as monotherapy was similar to the combination of ABA+methotrexate (MTX) for ACR50 (RR: 0.82 [95% CI 0.51-1.35]), and DAS28 remission (RR: 0.69 [95% CI 0.37-1.3]), as well as for withdrawal due to AEs (RR: 2.35 [95% CI 0.69-7.38]) and all-cause withdrawal (RR: 1.73 [95% CI 0.905-3.35]). ABA as monotherapy and ABA+MTX were both comparable to all other therapies for the main efficacy and safety outcomes. Observational study data reported was congruous with the RCT analysis. CONCLUSIONS: The results of this NMA show similar efficacy and safety between ABA (as monotherapy or in combination with MTX) and other biologics in early RA. Further comparison of different treatment options for early RA is warranted as growing research provides evidence for the application of new novel therapies for RA.


Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Abatacepte/efeitos adversos , Adulto , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Quimioterapia Combinada , Humanos , Metotrexato/efeitos adversos , Metanálise em Rede
9.
Value Health ; 23(4): 461-470, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32327163

RESUMO

OBJECTIVES: Biologic disease-modifying antirheumatic drugs (bDMARDs) are prescribed sequentially in the treatment of rheumatoid arthritis (RA). Healthcare decision makers continue to debate their use, mainly because of their high costs. Our aim was to perform an economic evaluation for France of bDMARD sequences for treatment of moderate-to-severe RA after inadequate response or intolerance to conventional DMARDs (eg, methotrexate). METHODS: A discretely integrated condition event simulation was developed to track the course of patients from first bDMARD through switches to further lines in a sequence. The model included 11 events, 91 conditions, and 21 controlling equations. Inputs were obtained from a meta-analysis of clinical trials, a French registry, national drug lists, and databases. Survival, time with minimal activity, quality-adjusted life-years (QALYs), and total costs were output. Structural and probabilistic sensitivity analyses were conducted. RESULTS: Sequences starting with etanercept biosimilars (ETB) cost less, with ETB-abatacept-infliximab the least expensive: the mean lifetime discounted total cost was €116 912 per patient, with a mean of 11.166 QALYs. Most other strategies were dominated or led to small QALY gains (0.0008-0.0329). Only ETB-tocilizumab-abatacept made it onto the efficiency frontier, but at €955 778 per QALY gained. These results were confirmed in several scenarios and uncertainty analyses. CONCLUSION: Given minor differences in QALYs gained between bDMARD sequences with large cost differences, starting with biosimilars was more efficient than starting with branded products. Our model and findings should provide French and other decision makers with useful tools to address the challenges of comparing sequences of treatments for RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Modelos Econômicos , Antirreumáticos/economia , Artrite Reumatoide/economia , Artrite Reumatoide/fisiopatologia , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/economia , Análise Custo-Benefício , França , Humanos , Metotrexato/efeitos adversos , Metotrexato/economia , Anos de Vida Ajustados por Qualidade de Vida , Índice de Gravidade de Doença
10.
Medicine (Baltimore) ; 99(15): e19850, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282749

RESUMO

RATIONALE: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a serious complication in patients treated using methotrexate. It occasionally develops in extra-nodal sites, but rarely in the central nervous system (CNS) or in 2 different sites at the same time. We present the rare case of a patient with rheumatoid arthritis who developed lymphoma in the CNS and stomach during MTX therapy. PATIENT CONCERNS: A 75-year-old Japanese man with rheumatoid arthritis who received methotrexate was admitted to our hospital because of gait ataxia and anorexia. DIAGNOSES: Imaging findings and biopsy led to a diagnosis of 2 different types of MTX-LPD in the central nervous system and stomach. INTERVENTIONS: The lesion in his stomach improved after methotrexate withdrawal, whereas the cerebellar mass required high-dose methotrexate and rituximab therapy. OUTCOMES: Complete remission has been maintained for the 2 years following the initiation of chemotherapy. LESSONS: In patients with RA who receive MTX and develop new neurological symptoms, CNS lymphoma as an MTX-LPD may be considered as a differential diagnosis.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Artrite Reumatoide/complicações , Neoplasias do Sistema Nervoso Central/patologia , Linfoma/induzido quimicamente , Metotrexato/efeitos adversos , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Diagnóstico Diferencial , Endoscopia do Sistema Digestório/métodos , Feminino , Marcha Atáxica/diagnóstico , Marcha Atáxica/etiologia , Humanos , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Resultado do Tratamento
12.
An Bras Dermatol ; 95(2): 150-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122693

RESUMO

BACKGROUND: Psoriasis is associated with atherosclerosis and increased cardiovascular risk. Currently, an automated ultrasound, called quantitative intima media thickness, has proven to be a useful method to evaluate subclinical atherosclerosis. OBJECTIVES: To compare increased cardiovascular risk in psoriasis patients receiving two types of treatments: Methotrexate and tumor necrosis factor inhibitor and to evaluate the correlation between the Framingham score and quantitative intima media thickness. METHODS: Fifty patients with plaque psoriasis were selected from June 2017 to July 2018, divided into two groups, receiving methotrexate and tumor necrosis factor inhibitor. Measurement of abdominal circumference, blood pressure, body mass index and presence of metabolic syndrome were performed. Afterwards, the patients were evaluated for increased cardiovascular risk with the Framingham score and for the quantitative intima media thickness of the carotid arteries. RESULTS: The mean age was 54.8 (±12.5) with a slight male predominance (58%). Overall, 84% of the patients had elevated waist circumference, 82% had a body mass index above ideal, and 50% had a metabolic syndrome. For the correlation between quantitative intima media thickness and Framingham Score, Pearson's linear correlation coefficient was 0.617 (p<0.001), indicating a moderate to strong positive association. STUDY LIMITATIONS: The protective effect of the therapies cited in relation to the increased cardiovascular risk was not evaluated. CONCLUSIONS: A moderate to strong positive association was found correlating the Framingham Score values with the quantitative intima media thickness measurement and it is not possible to state which drug has the highest increased cardiovascular risk.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Espessura Intima-Media Carotídea , Fármacos Dermatológicos/efeitos adversos , Metotrexato/efeitos adversos , Psoríase/complicações , Psoríase/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Adulto , Idoso , Índice de Massa Corporal , Brasil/epidemiologia , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/epidemiologia , Valores de Referência , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Circunferência da Cintura
13.
J Pharmacol Sci ; 143(1): 30-38, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32151540

RESUMO

The role of nitric oxide (NO) on intestinal mucosal injury induced by single or consecutive administration of methotrexate was investigated in a rodent model. Rats received methotrexate intraperitoneally either as a single administration (50 mg/kg) or as a consecutive administration (12.5 mg/kg/day) for 4 days. NG-nitro-l-arginine methyl ester (L-NAME) was given subcutaneously to inhibit NO synthase (NOS). Ninety-six hours after the first administration of methotrexate, ileal tissues were collected for analysis. Consecutive administration of methotrexate led to decreased body weight and reduced intake of food and water, which were further worsened by L-NAME. Although a slight mucosal injury resulted from single administration of methotrexate, L-NAME had almost no effect. Consecutive administration of methotrexate caused a significant mucosal injury, which was further worsened by L-NAME. Consecutive, but not single, administration of methotrexate induced mRNA expression of inflammatory cytokines in ileal tissue. Consecutive administration of methotrexate significantly induced constitutive NOS expression in ileal tissue. These results suggest that consecutive administration, rather than single administration, of methotrexate aggravates mucosal injury. Potentiation of constitutive NOS expression by consecutive administration might be one of the main reason to antagonize the intestinal mucosal injury as well as lead to a reduction in rat quality of life.


Assuntos
Expressão Gênica , Enteropatias/etiologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Óxido Nítrico/efeitos adversos , Óxido Nítrico/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Modelos Animais , Óxido Nítrico/genética , RNA Mensageiro/metabolismo , Ratos Wistar
15.
Medicine (Baltimore) ; 99(8): e19193, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080104

RESUMO

BACKGROUND: This meta-analysis aimed to explore the efficacy and safety of rituximab combined with methotrexate (MTX) versus MTX alone in the treatment of rheumatoid arthritis (RA). METHODS: We performed an electronic search of PubMed (1950-January 2018), EMBASE (1974-January 2018), the Cochrane Library (January 2018 Issue 3), the Google database (1950-January 2018), and the Chinese Wanfang database (1950-January 2018). Only randomized controlled trials (RCTs) were included. The American College of Rheumatology 20% improvement criteria (ACR20), ACR50, ACR70, total complication rate, and infection rate were the outcomes. A fixed/random effects model was used according to the heterogeneity assessed by the I statistic. Data analysis was performed using Stata 12.0 software. RESULTS: A total of five RCTs with 3299 patients (rituximab combined with MTX group = 1787, MTX only group = 1512) were included in the meta-analysis. The pooled risk ratio showed that the administration of rituximab combined with MTX was associated with more ACR20, ACR50, and ACR70 than the administration of MTX only (P < .05). There were no significant differences between the two groups in terms of the total complication rate and the infection rate (P > .05). CONCLUSION: The administration of rituximab combined with MTX was effective and safe for RA patients. Additional high-quality RCTs with long-term follow-ups should be conducted in the future to identify the potential complications in the long term.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Rituximab/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Produtos Biológicos/uso terapêutico , Quimioterapia Combinada , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/administração & dosagem
16.
Ann Intern Med ; 172(6): 369-380, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066146

RESUMO

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Design: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). Setting: North America. Participants: Adults with known cardiovascular disease and diabetes or metabolic syndrome. Intervention: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Measurements: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. Results: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). Limitation: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. Conclusion: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. Primary Funding Source: National Institutes of Health.


Assuntos
Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos
17.
Am J Gastroenterol ; 115(4): 526-534, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32022719

RESUMO

Half of patients with inflammatory bowel disease (IBD) are men, yet less attention has been focused on their sexual issues despite higher rates of sexual dysfunction and infertility than the general population. Depression and IBD disease activity are the most consistently reported risk factor for sexual dysfunction among men with IBD. Methotrexate and sulfasalazine have been rarely associated with impotence. Sulfasalazine reversibly reduces male fertility. No other medications used in IBD significantly affect fertility in humans. There is no increase in adverse fetal outcomes among offspring of fathers with IBD. Patients with IBD seem to be at a higher risk for prostate cancer; therefore, screening as recommended for high-risk patients should be considered.


Assuntos
Infertilidade Masculina/induzido quimicamente , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neoplasias da Próstata/etiologia , Disfunções Sexuais Fisiológicas/etiologia , Depressão/complicações , Fármacos Gastrointestinais/efeitos adversos , Humanos , Infertilidade Masculina/etiologia , Masculino , Metotrexato/efeitos adversos , Fatores de Risco , Sulfassalazina/efeitos adversos
19.
Adv Clin Exp Med ; 29(1): 5-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31965764

RESUMO

BACKGROUND: Methotrexate (MTX) is an antineoplastic agent, which increases the level of reactive oxygen species (ROS) and decreases the level of antioxidants. Lycopene, is a potent antioxidant, which is used because of its protective effect against tissue damage. OBJECTIVES: The aim of this study was to determine the effect of lycopene on ovarian MTX-induced injury in rats. MATERIAL AND METHODS: Rats (n = 36) were randomly divided into 3 equal groups: a group with MTX only (MG, n = 12), a group with lycopene and MTX (LMG, n = 12), and a healthy control group (HCG, n = 12). Then, malondialdehyde (MDA), myeloperoxidase (MPO) and total glutathione (tGSH) levels and histopathological findings were examined in the ovaries of rats. Apart from the histopathological and biochemical evaluation, the reproductive performance of the experimental groups was also examined. RESULTS: Our study demonstrated that, in ovarian tissues of rats administered MTX, there was a decrease in the levels of tGSH, while MDA and MPO were increased, but it is observed that these ratios are reversed in the LMG (p < 0.05). It also has been proven that a single, high-dose use of MTX causes infertility in female rats, prolongs the gestation period and reduces the number of offspring. CONCLUSIONS: Lycopene pretreatment ameliorates the MTX induced ovarian injury and infertility in rats through its antioxidative activities.


Assuntos
Antimetabólitos Antineoplásicos , Antioxidantes , Infertilidade Feminina , Licopeno , Metotrexato , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Feminino , Glutationa , Infertilidade Feminina/induzido quimicamente , Infertilidade Feminina/prevenção & controle , Licopeno/uso terapêutico , Malondialdeído , Metotrexato/efeitos adversos , Ovário/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Wistar
20.
Yakugaku Zasshi ; 140(1): 15-22, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902879

RESUMO

The development of serious lung diseases, such as pulmonary fibrosis, is associated with several drugs. A recent study has shown that the epithelial-mesenchymal transition (EMT) plays an essential role in the development of pulmonary fibrosis. However, the mechanisms underlying drug-induced EMT in alveolar epithelial cells have not been characterized. The present study showed that methotrexate (MTX), a drug known to cause lung injury, induced EMT-like phenotypic changes in an A549 cell model of the alveolar epithelium. We also found that the transforming growth factor (TGF)-ß1-mediated signaling pathway was associated with MTX-induced EMT. In addition, our results showed that certain secreted factors and microRNAs, a class of small noncoding RNAs, may be involved in MTX-induced EMT. The effects of COA-Cl, a novel synthetic small molecule, on TGF-ß1-induced EMT were evaluated to determine the therapeutic potential of COA-Cl against drug-induced lung injury. COA-Cl significantly suppressed TGF-ß1-induced EMT-like phenotypic changes, as evidenced by the inhibition of EMT-related transcription factors. Furthermore, MTX-induced EMT was completely suppressed by co-treatment with folic acid. Thus, these compounds may be promising therapeutic agents against drug-induced lung injury. In conclusion, the present study elucidated mechanisms underlying drug-induced EMT and highlighted a potential novel therapeutic approach to drug-induced lung diseases.


Assuntos
Lesão Pulmonar/induzido quimicamente , Metotrexato/efeitos adversos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/uso terapêutico , Humanos , Lesão Pulmonar/tratamento farmacológico , MicroRNAs , Terapia de Alvo Molecular , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/fisiologia
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