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1.
Pediatr Rheumatol Online J ; 17(1): 57, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438986

RESUMO

BACKGROUND: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. METHODS: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group). RESULTS: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] µg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group). CONCLUSIONS: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years. CLASSIFICATION: Juvenile idiopathic arthritis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Esquema de Medicação , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento
2.
Pharm Res ; 36(8): 123, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31218557

RESUMO

PURPOSE: This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA). METHODS: To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance. RESULTS: fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6 nm in size with 0.109 PDI, 8.01 ± 0.3 mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24 h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints. CONCLUSIONS: The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.


Assuntos
Anti-Inflamatórios/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Ácido Fólico/química , Lipossomos/química , Metotrexato/farmacocinética , Prednisolona/farmacocinética , Animais , Anti-Inflamatórios/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Quimioterapia Combinada , Humanos , Masculino , Metotrexato/administração & dosagem , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Prednisolona/administração & dosagem , Ratos , Propriedades de Superfície , Distribuição Tecidual
3.
Scand J Rheumatol ; 48(5): 362-366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31244356

RESUMO

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).


Assuntos
Anticorpos/sangue , Artrite Reumatoide/tratamento farmacológico , Infliximab/farmacocinética , Fator Reumatoide/sangue , Anticorpos/imunologia , Antirreumáticos/imunologia , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Infliximab/imunologia , Masculino , Metotrexato/uso terapêutico , Falha de Tratamento
4.
Reumatol. clín. (Barc.) ; 15(3): 133-139, mayo-jun. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-184364

RESUMO

Objective: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). Methods: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. Results: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. Conclusion: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints


Objetivo: Evaluar la eficacia y los efectos secundarios del metotrexato o la leflunomida en pacientes con AR como primer fármaco modificador de la enfermedad (FAME). Métodos: Se realizó una revisión sistemática y metaanálisis de estudios clínicos que incluyeron a pacientes que tomaron metotrexato, leflunomida, placebo u otro FAME para el tratamiento de la AR. Después de una revisión sistemática, se encontraron 1.971 artículos, una vez revisados completamente, se seleccionaron 73 ensayos que completaron los criterios de inclusión. En talleres estructurados para el debate y la evaluación de cada artículo, 6 pudieron ser metaanalizados para los resultados primarios y secundarios: logro de ACR 20 y sus componentes básicos, así como el cambio de los niveles séricos de PCR, HAQ-DI, enzimas hepáticas AST/ALT, nuevos efectos secundarios gastrointestinales (GI) e infecciones. Resultados: Se incluyó a un total de 1.984 pacientes, 986 tomaron leflunomida y 998 metotrexato. La probabilidad de alcanzar ACR 20 reveló una OR 0,88 (IC del 95%: 0,74; 1,06) con una tendencia a favorecer el metotrexato; la reducción del recuento de articulaciones inflamadas fue mayor para metotrexato: diferencia de medias (MD)=0,82 (IC del 95%: 0,24, 1,39); el recuento de articulaciones sensibles, la evaluación global de médicos, el HAQ-DI, y los niveles séricos de PCR no revelaron diferencias entre los grupos. El aumento de las enzimas hepáticas fue más frecuente en el grupo con leflunomida, OR=0,38 (IC del 95%: 0,27, 0,53) y las nuevas quejas GI fueron más frecuentes en el metotrexato, OR=1,44 (IC del 95% 1,17, 1,79). No hubo diferencias en la incidencia de infecciones no graves. Conclusión: La leflunomida utilizada como el primer FAME en la AR parece ser tan eficaz como el metotrexato; solo la reducción de las articulaciones inflamadas fue mayor para el metotrexato. La leflunomida está relacionada con una mayor elevación de las enzimas hepáticas, pero presenta menos molestias GI


Assuntos
Humanos , Leflunomida/farmacocinética , Metotrexato/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/farmacocinética , Leflunomida/efeitos adversos , Metotrexato/efeitos adversos , Segurança do Paciente/estatística & dados numéricos , Resultado do Tratamento
5.
Pediatr Rheumatol Online J ; 17(1): 17, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039807

RESUMO

BACKGROUND: To investigate efficacy and safety of intravenous abatacept in Japanese patients with active polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: In this phase III, open-label, multicenter, single-arm study, patients with pJIA aged 4-17 years who failed ≥1 biologic or methotrexate received weight-tiered (< 75 kg: 10 mg/kg; 75-100 kg: 750 mg; > 100 kg: 1000 mg) intravenous abatacept at Weeks 0, 2, 4, and every 4 weeks thereafter. The study comprised a short-term period (16 weeks) and ongoing long-term period. Primary endpoint: Week 16 JIA-American College of Rheumatology criteria 30 (JIA-ACR30) response rate. Secondary endpoints/outcomes included Week 16 JIA-ACR50/70/90 response and inactive disease rates, Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), pharmacokinetics, safety, and immunogenicity. Proportions of patients achieving Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP) remission (score < 1) and minimal disease activity (MDA; score < 3.8), were among exploratory endpoints. RESULTS: All 20 patients who received study medication completed the short-term period. During the long-term period, two patients discontinued due to insufficient efficacy or patient decision. Median age and disease duration at baseline were 10.5 and 0.75 years, respectively. Week 16 JIA-ACR30 response rate (primary endpoint) was 90.0% (18/20). JIA-ACR50/70/90 response and inactive disease rates at Week 16 were 75.0% (15/20), 70.0% (14/20), 35.0% (7/20), and 25.0% (5/20), respectively. At Week 52, JIA-ACR30/50/70/90 response and inactive disease rates were observed by 88.9% (16/18), 88.9% (16/18), 83.3% (15/18), 66.7% (12/18) and 44.4% (8/18), respectively. CHAQ-DI improved after Week 12. JADAS27-CRP remission and MDA were achieved by 15.0% (3/20) and 45.0% (9/20) of patients at Week 16, and by 50.0% (9/18) and 78.0% (14/18) of patients at Week 52, respectively. The mean abatacept pre-dose serum concentration was above the target therapeutic exposure (10 µg/ml) from Week 8 through Week 16. All adverse events were of mild/moderate intensity, except for one case of severe gastroenteritis. No deaths, malignancies, or autoimmune disorders were observed. No antidrug antibodies were detected through Week 16; one patient had a positive immunogenic response during the cumulative period. CONCLUSION: Intravenous abatacept was efficacious and well tolerated in Japanese patients with active pJIA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01835470 . Date of registration: April 19, 2013.


Assuntos
Abatacepte/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Abatacepte/efeitos adversos , Abatacepte/farmacocinética , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Fatores de Tempo , Resultado do Tratamento
6.
J Pharmacol Exp Ther ; 369(3): 406-418, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940693

RESUMO

The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis. A range of doses of indomethacin (a nonsteroidal anti-inflammatory drug), and three disease-modifying antirheumatic drugs (DMARDs), methotrexate, etanercept, and tofacitinib, were evaluated in AIA and CIA rats. Dexamethasone was included in this study as a positive control. The area under the ankle diameter-time profile (AUCankle) and ankle histopathology summed scores (AHSS) were used as efficacy endpoints for activity against disease symptoms (joint inflammation) and disease progression (joint damage), respectively. Translational PK-PD analysis was performed to rank order preclinical efficacy endpoints at clinically relevant concentrations. For each drug tested, inhibition of AUCankle and AHSS scores was generally comparable in both magnitude and rank order. Overall, based on both AUCankle and the AHSS inhibition, the rank ordering of preclinical activity for the DMARDs evaluated was tofacitinib > etanercept ≥ methotrexate. This ranking of preclinical efficacy was consistent with reported clinical efficacy. Of interest, indomethacin showed equal or often better efficacy than the three DMARDs evaluated on inhibiting AHSS despite having limited ability to prevent joint damage clinically in patients. The translational value of performing PK-PD analysis of arthritis models in rats is discussed.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Antirreumáticos/farmacologia , Antirreumáticos/farmacocinética , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Pesquisa Médica Translacional , Animais , Tornozelo/patologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Experimental/patologia , Relação Dose-Resposta a Droga , Masculino , Ratos
7.
Int J Rheum Dis ; 22(6): 1130-1137, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968569

RESUMO

AIMS: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, is used to treat rheumatic diseases. There is limited information about the administration of TCZ during lactation. The dried spot method, a simple technique for processing biological samples which involves placement of a drop of specimen onto filter paper, has been used in clinical pharmacology to determine various drug concentrations. This study examined the feasibility of sample collection using the dried milk spot (DMS) method for obtaining data about the transfer of TCZ into breast milk. METHODS: Concentrations of TCZ determined using DMSs prepared by patients were compared with those using liquid breast milk. RESULTS: In an enzyme-linked immunosorbent assay of TCZ in DMSs, the accuracy ranged from 93.0% to 113.8% and the precision ranged from 0.3% to 8.4%. All concentrations of TCZ were within 15% of the reference value when analyzed on separate days. TCZ in DMSs at room temperature, 4°C, and -20°C were stable for 28 days. Extracted TCZ concentrations from patient-prepared DMSs were strongly correlated with those of liquid samples (r = 0.996). In a pharmacokinetic study, the median (range) maximum and minimum concentrations were 113 ng/mL (68-205) and 8.5 ng/mL (4.8-13.4), respectively. The milk-to-serum ratio at the trough TCZ concentration of 3 lactating mothers were 0.0015, 0.00082 and 0.0014. CONCLUSIONS: The DMS method for measuring TCZ transfer into breast milk may be reliable and feasible, and should contribute to evaluating the safety of breast-fed infants whose mothers receive TCZ during lactation.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Lactação , Leite Humano/metabolismo , Adulto , Anticorpos Monoclonais Humanizados/sangue , Antirreumáticos/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Ensaio de Imunoadsorção Enzimática , Estudos de Viabilidade , Feminino , Humanos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
8.
Clin Rheumatol ; 38(1): 63-70, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29611087

RESUMO

The aim of the present study was to compare long-term adalimumab (ADA) and infliximab (IFX) retention rates in patients with intermediate, posterior, or panuveitis. Additional aims are as follows: (i) to identify any difference in the causes of treatment discontinuation between patients treated with ADA and IFX; (ii) to assess any impact of demographic features, concomitant treatments, and different lines of biologic therapy on ADA and IFX retention rates; and (iii) to identify any correlation between ADA and IFX treatment duration and the age at uveitis onset, the age at onset of the associated systemic diseases, and the age at the start of treatment. Clinical, therapeutic, and demographic data from patients with non-infectious intermediate, posterior, or panuveitis treated with ADA or IFX were retrospectively collected. Kaplan-Meier plot and log-rank (Mantel-Cox) test were used to assess survival curves. One hundred eight patients (188 eyes) were enrolled; in 87 (80.6%) patients, uveitis was associated with a systemic disease. ADA and IFX were administered in 62 and 46 patients, respectively. No statistically significant differences were identified between ADA and IFX retention rates (p value = 0.22). Similarly, no differences were identified between ADA and IFX retention rates in relation to gender (p value = 0.61 for males, p value = 0.09 for females), monotherapy (p value = 0.08), combination therapy with conventional disease-modifying antirheumatic drugs (log-rank p value = 0.63), and different lines of biologic therapy (p value = 0.79 for biologic-naïve patients; p value = 0.81 for subjects previously treated with other biologics). In conclusion, ADA and IFX have similar long-term retention rates in patients with non-infectious intermediate, posterior, and panuveitis. Demographic, clinical, and therapeutic features do not affect their long-term effectiveness.


Assuntos
Adalimumab/farmacocinética , Antirreumáticos/farmacocinética , Infliximab/farmacocinética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/tratamento farmacológico , Adalimumab/uso terapêutico , Adulto , Antirreumáticos/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Itália , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
9.
Mol Pharm ; 16(1): 273-281, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30550295

RESUMO

Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [124I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [124I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [124I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [124I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [124I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [124I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Interleucina-10/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Humanos , Interleucina-10/genética , Fígado/metabolismo , Masculino , Camundongos , Ratos , Baço/metabolismo
10.
Int J Rheum Dis ; 22(3): 376-385, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28332780

RESUMO

Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are recommended for the medium- to long-term management of knee osteoarthritis (OA) due to their abilities to control pain, improve function and delay joint structural changes. Among SYSADOAs, evidence is greatest for the patented crystalline glucosamine sulfate (pCGS) formulation (Mylan). Glucosamine is widely available as glucosamine sulfate (GS) and glucosamine hydrochloride (GH) preparations that vary substantially in molecular form, pharmaceutical formulation and dose regimen. Only pCGS is given as a highly bioavailable once-daily dose (1500 mg), which consistently delivers the plasma levels of around 10 µmol/L required to inhibit interleukin-1-induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction. Careful consideration of the evidence base reveals that only pCGS reliably provides a moderate effect size on pain that is higher than paracetamol and equivalent to non-steroidal anti-inflammatory drugs (NSAIDs), while non-crystalline GS and GH fail to reach statistical significance for pain reduction. Chronic administration of pCGS has disease-modifying effects, with a reduction in need for total joint replacement lasting for 5 years after treatment cessation. Pharmacoeconomic studies of pCGS demonstrate long-term reduction in additional pain analgesia and NSAIDs, with a 50% reduction in costs of other OA medication and healthcare consultations. Consequently, pCGS is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression. Physician and patient education on the differentiation of pCGS from other glucosamine formulations will help to improve treatment selection, increase treatment adherence, and optimize clinical benefit in OA.


Assuntos
Antirreumáticos/uso terapêutico , Glucosamina/uso terapêutico , Osteoartrite/tratamento farmacológico , Patentes como Assunto , Animais , Antirreumáticos/efeitos adversos , Antirreumáticos/economia , Antirreumáticos/farmacocinética , Análise Custo-Benefício , Cristalização , Composição de Medicamentos , Custos de Medicamentos , Glucosamina/efeitos adversos , Glucosamina/economia , Glucosamina/farmacocinética , Humanos , Osteoartrite/diagnóstico , Osteoartrite/economia , Educação de Pacientes como Assunto , Resultado do Tratamento
11.
Nat Commun ; 9(1): 4291, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327464

RESUMO

Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/genética , Ácidos Nucleicos Livres/efeitos adversos , Inflamação/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antirreumáticos/química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Cátions/química , Ácidos Nucleicos Livres/isolamento & purificação , Feminino , Humanos , Inflamação/etiologia , Injeções Intravenosas , Metacrilatos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/metabolismo , Nylons/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos Endogâmicos Lew , Líquido Sinovial/citologia , Distribuição Tecidual , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/metabolismo
12.
Int J Clin Pharmacol Ther ; 56(11): 507-517, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30168415

RESUMO

OBJECTIVE: Namilumab is an investigational human monoclonal antibody to human granulocyte-macrophage colony-stimulating factor (GM-CSF). A phase I study of repeated namilumab dosing (150 or 300 mg subcutaneously) in non-Japanese patients with rheumatoid arthritis reported no safety concerns. The objective of this study was to report the safety (primary endpoint) and pharmacokinetic/pharmacodynamic effects of namilumab in healthy Japanese and Caucasian men aged 20 - 45 years (NCT02354599). MATERIALS AND METHODS: 24 Japanese subjects were randomized to a single dose of namilumab (80, 150, or 300 mg; n = 6/group) or placebo (n = 6; 2 subjects randomized/matched dose); 8 Caucasian subjects received namilumab 150 mg (n = 6) or placebo (n = 2). RESULTS: Overall, 29 subjects completed the study (2 withdrew voluntarily; 1 due to a serious adverse event (AE) unrelated to treatment). Baseline demographics were similar across treatment groups; mean age and weight were higher in Caucasians. Namilumab was well tolerated, with no notable safety concerns or pharmacokinetic/pharmacodynamic differences between Japanese and Caucasian subjects. AEs were mild to moderate, with no dose-proportional increase in Japanese subjects. Area under the serum concentration-time curve from zero to infinity (AUC0-∞) and maximum serum concentration (Cmax) increased in a dose-proportional manner in Japanese subjects. AUC0-∞ was similar in Japanese (575.2 µg×day/mL) and Caucasian (559.7 µg×day/mL) 150-mg groups. Cmax was ~ 40% higher in Japanese subjects. Mean plasma total GM-CSF concentration-time profiles were similar in the Japanese and Caucasian 150-mg groups. Namilumab induced no clinically-relevant antibody response. CONCLUSION: Namilumab was well tolerated in Japanese and Caucasian subjects; namilumab 150 mg had similar pharmacokinetics in both populations, supporting further clinical development of this dose.
.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antirreumáticos/farmacocinética , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Pharm Res ; 35(11): 201, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30187188

RESUMO

PURPOSE: The present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity. METHODS: Drug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO. RESULTS: The size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP. CONCLUSIONS: We report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects. Graphical Abstract ᅟ.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Crotonatos/administração & dosagem , Durapatita/química , Metotrexato/administração & dosagem , Nanopartículas/química , Toluidinas/administração & dosagem , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Crotonatos/farmacocinética , Crotonatos/farmacologia , Portadores de Fármacos , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Concentração de Íons de Hidrogênio , Cinética , Metotrexato/farmacocinética , Metotrexato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos , Ratos Wistar , Distribuição Tecidual , Toluidinas/farmacocinética , Toluidinas/farmacologia
14.
Eur J Med Chem ; 158: 502-516, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30243154

RESUMO

Methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) because of its potent efficacy and tolerability. MTX benefits a large number of RA patients but partially suffered from side effects. A variety of side effects can be associated with MTX when treating RA patients, from mild to severe or discontinuation of the treatment. In this report, we reviewed the possible side effects that MTX might cause from the most common gastrointestinal toxicity effects to less frequent malignant diseases. In order to achieve regimen with less side effects, the administration of MTX with appropriate dose and a careful pretreatment inspection is necessary. Further investigations are required when combining MTX with other drugs so as to enhance the efficacy and reduce side effects at the same time. The management of MTX treatment is also discussed to provide strategies for occurred side effects. Thus, this review will provide scholars with a comprehensive understanding the side effects of MTX administration by RA patients.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Metotrexato/efeitos adversos , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Gastroenteropatias/induzido quimicamente , Humanos , Metotrexato/farmacocinética , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Neoplasias/induzido quimicamente
15.
Life Sci ; 209: 228-235, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30096386

RESUMO

AIMS: Sinomenine, an anti-rheumatoid arthritis drug used in China for decades, is usually co-administered with cardiovascular (CV) drugs to reduce arthritis-related risk of cardiovascular diseases. This study was to investigate whether and how CV drugs affect the pharmacokinetic profile of sinomenine. MAIN METHODS: In rat liver microsomes (RLMs), the key metabolic enzymes of sinomenine were identified by using specific inhibitors. The influences of CV drugs, including propranolol, verapamil, warfarin, atorvastatin, simvastatin, and lovastatin, on the metabolism of sinomenine were examined. Cocktail probe, RT-qPCR, and western blotting were performed to unveil the underlying mechanism of the drug-drug interaction. KEY FINDINGS: The key metabolic enzymes of sinomenine were identified to be CYP3A1/2 and CYP2D1 in RLMs. Among the CV drugs screened, simvastatin and lovastatin were shown to inhibit the liver metabolism of sinomenine with Ki values of 13.00 and 25.83 µM, respectively. Single administration of simvastatin or lovastatin in rats increased the AUC value of sinomenine to 1.40- or 1.50-fold, and decreased the CLz/F value to 68.19% or 65.44%, respectively. In contrast, multiple administrations of simvastatin, but not lovastatin, increased the CLz/F value of sinomenine to 1.38-fold and decreased the AUC value to 71.59%. Further studies showed that the long-term administration of simvastatin could up-regulate the expression of CYP3A1/2 to account for the effect. SIGNIFICANCE: This study demonstrated the potential effect of simvastatin and lovastatin on the metabolism of sinomenine for the first time. The findings provide guidelines for the co-administration of sinomenine with simvastatin or lovastatin in clinic.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Lovastatina/administração & dosagem , Microssomos Hepáticos/metabolismo , Morfinanos/farmacocinética , Sinvastatina/administração & dosagem , Animais , Antirreumáticos/farmacocinética , Combinação de Medicamentos , Interações de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
16.
MAbs ; 10(6): 934-943, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30010481

RESUMO

This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC0-∞), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80-125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was -2.13 (0.175) for CT-P10 and -2.09 (0.176) for RTX. The 95% CI (-0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (-0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Rituximab/uso terapêutico , Adulto , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/farmacocinética , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Área Sob a Curva , Artrite Reumatoide/metabolismo , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/efeitos adversos , Rituximab/farmacocinética , Equivalência Terapêutica , Resultado do Tratamento
17.
Arthritis Res Ther ; 20(1): 155, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053896

RESUMO

BACKGROUND: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%). RESULTS: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.


Assuntos
Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/uso terapêutico , Infliximab/farmacocinética , Infliximab/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Equivalência Terapêutica
18.
Eur J Pharm Biopharm ; 130: 39-47, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29928978

RESUMO

Methotrexate (MTX), as a disease modifying antirheumatic drug (DMARD), was first line drug to treat rheumatoid arthritis. However, the severe side effect during long term and high dosage usage limit its application. The aim of this study was to develop dual-functional lipid polymeric hybrid pH-responsive nanoparticles to deliver MTX to inflamed joints selectively. The designed MTX loaded stearic acid-octa-arginine and folic acid decorated poly lactic-co-glycolic acid (PLGA) -PK3-based lipid polymeric hybrid nanoparticles (Sta-R8-FA-PPLPNs/MTX) were composed of PK3, Folate-PEG-PLGA, egg PC, and Sta-R8. The nanoparticles exhibited smooth spherical morphology and particle size of 100-150 nm. The in vitro release study indicated that MTX was released faster in phosphate buffered solution (PBS) of pH 5.0 than that in PBS of pH 7.4 from Sta-R8-FA-PPLPNs/MTX. The cellular uptake study revealed that Sta-R8-FA-PPLPNs/MTX were internalized through folate receptor mediated endocytosis into activated macrophages. Therapeutic effects on adjuvant-induced arthritis (AIA) rats further confirm that Sta-R8-FA-PPLPNs/MTX could be promising against rheumatoid arthritis.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Nanopartículas , Animais , Antirreumáticos/farmacocinética , Arginina/química , Artrite Experimental/tratamento farmacológico , Peptídeos Penetradores de Células/química , Portadores de Fármacos/química , Ácido Fólico/química , Concentração de Íons de Hidrogênio , Ácido Láctico/química , Lipídeos/química , Masculino , Metotrexato/farmacologia , Camundongos , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polímeros/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Ácidos Esteáricos/química
19.
Nat Rev Rheumatol ; 14(7): 393-403, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29899547

RESUMO

Developing therapeutic molecules that target chondrocytes and locally produced inflammatory factors within arthritic cartilage is an active area of investigation. The extensive studies that have been conducted over the past 50 years have enabled the accurate prediction and reliable optimization of the transport of a wide variety of molecules into cartilage. In this Review, the factors that can be used to tune the transport kinetics of therapeutics are summarized. Overall, the most crucial factor when designing new therapeutic molecules is solute size. The diffusivity and partition coefficient of a solute both decrease with increasing solute size as indicated by molecular mass or by hydrodynamic radius. Surprisingly, despite having an effective pore size of ~6 nm, molecules of ~16 nm radius can diffuse through the cartilage matrix. Alteration of the shape or charge of a solute and the application of physiological loading to cartilage can be used to predictably improve solute transport kinetics, and this knowledge can be used to improve the development of therapeutic agents for osteoarthritis that target the cartilage.


Assuntos
Antirreumáticos/farmacocinética , Artrite/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Animais , Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite/diagnóstico por imagem , Transporte Biológico , Cartilagem Articular/diagnóstico por imagem , Desenho de Drogas , Humanos
20.
Drugs ; 78(6): 611-619, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29616495

RESUMO

Methotrexate is known to be safe and efficacious in the management of rheumatoid arthritis and psoriasis and thus has been used for the management of psoriatic arthritis despite a lack of evidence to support efficacy in psoriatic arthritis from randomized controlled trials. Although the largest randomized trial to date did not support its use as a disease-modifying therapy, observational studies have supported its role, and current treatment recommendations approve of its use as a first-line agent for the management of psoriatic arthritis with predominant peripheral arthritis. The first treat-to-target study in psoriatic arthritis, comparing tight control with standard care, has shown the efficacy of methotrexate as monotherapy in the first 12 weeks. This trial demonstrated the effectiveness of methotrexate with improvement in peripheral arthritis, skin and nail disease, enthesitis, and dactylitis over the course of 12 weeks. There is conflicting evidence about the role of combination (concomitant methotrexate and anti-tumor necrosis factor) therapy. However, drug survival and immunogenicity of certain anti-tumor necrosis factors seem to be better when used in combination with methotrexate. This report reviews the available evidence on the efficacy and effectiveness of methotrexate in psoriatic arthritis and its role in treating psoriatic arthritis to target, as well as in combination with biologic agents. Ideally, randomized placebo-controlled clinical trials evaluating methotrexate (using subcutaneous route of delivery) would provide much-needed clarity on the role of methotrexate in the management of psoriatic arthritis; however, issues around using a placebo in patients with active psoriatic arthritis may render such a trial unfeasible.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Metotrexato/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antirreumáticos/química , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Quimioterapia Combinada , Humanos , Metotrexato/química , Metotrexato/farmacocinética
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