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1.
Arq Gastroenterol ; 56(4): 351-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618395

RESUMO

BACKGROUND: Physical activity in daily life and exercise capacity have not been assessed in patients with Crohn's disease to date. OBJECTIVE: To evaluate the physical activity in daily life, exercise capacity, quality of life, and prevalence of mood disorders in patients with moderate-to-severe Crohn's disease on infliximab-induced remission and the possible associations among variables. METHODS: A cross-sectional preliminary study was conducted. Twenty-six patients with Crohn's disease and 20 controls were selected. Participants underwent evaluation of physical activity in daily life (triaxial accelerometer), exercise capacity (shuttle walk test), handgrip strength, quality of life, and presence of mood disorders. RESULTS: The number of steps taken (7446±3081 vs 7898±2487), active time (80.6±42 vs 89.7±24.3min), shuttle walk test distance [665 (405) vs 710 (409) m] and handgrip strength [31 (15) vs 29 (20) kgf did not show any difference between the patients with Crohn's disease and the controls. The time spent lying down [95.8 (68.8) vs 60.9 (74.7) min] was greater and some domains of the quality of life were superior in the patients with Crohn's disease. No correlation was observed between the physical activity in daily life and quality of life or presence of mood disorders in patients with Crohn's disease. CONCLUSION: Patients with Crohn's disease on infliximab-induced remission, despite to more time spent lying down, they have the same level of physical activity in daily life and exercise capacity min compared with the controls.


Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/psicologia , Exercício/psicologia , Fármacos Gastrointestinais/administração & dosagem , Infliximab/administração & dosagem , Transtornos do Humor/psicologia , Qualidade de Vida/psicologia , Adulto , Estudos de Casos e Controles , Doença de Crohn/radioterapia , Estudos Transversais , Tolerância ao Exercício , Feminino , Humanos , Masculino , Prevalência , Índice de Gravidade de Doença
2.
Gastroenterology ; 157(5): 1338-1351.e8, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401142

RESUMO

BACKGROUND & AIMS: Some patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in the treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation. METHODS: C57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab')2 fragments. Blood samples were collected every 2-3 days for 2 weeks and weekly thereafter for up to 6 weeks; infliximab-TNF complexes and ADAs were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal biopsy and blood samples were obtained from patients having endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab-TNF complexes were measured with ELISA. Infliximab-specific plasma cells were detected in patient tissue samples by using mass cytometry. We studied activation of innate immune cells in peripheral blood mononuclear cells (PBMCs) from healthy donors incubated with infliximab or infliximab-TNF complexes; toll-like receptors (TLRs) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time polymerase chain reaction and ELISAs. Uptake of infliximab and infliximab-TNF complexes by THP-1 cells was measured with confocal microscopy. RESULTS: Mice given increasing doses of infliximab produced increasing levels of ADAs. Blood samples from mice given injections of human TNF and infliximab contained infliximab-TNF complexes; complex formation was associated with ADA formation with an area under the curve of 0.944 (95% confidence interval, 0.851-1.000; P = .003). Intestinal tissues from patients, but not blood samples, contained infliximab-TNF complexes and infliximab-specific plasma cells. Incubation of PBMCs with infliximab-TNF complexes resulted in a 4.74-fold increase in level of interleukin (IL) 1ß (IL1B) messenger RNA (P for comparison = .005), increased IL1B protein secretion, and a 2.69-fold increase in the expression of TNF messenger RNA (P for comparison = 0.013) compared with control PBMCs. Infliximab reduced only IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone. CONCLUSIONS: In mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab-TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab-TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug-TNF complex.


Assuntos
Anticorpos/sangue , Fragmentos Fab das Imunoglobulinas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Infliximab/imunologia , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Estudos de Casos e Controles , Endocitose , Feminino , Humanos , Imunidade Inata , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/administração & dosagem , Injeções Intravenosas , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Células THP-1 , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo
3.
Drug Discov Ther ; 13(3): 164-167, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31257354

RESUMO

Immune checkpoint inhibitors are associated with a wide spectrum of immune-related adverse events (irAEs) that are typically transient but are sometimes severe or even fatal. No consensus exists for the treatment of severe immune-mediated pneumonitis that is refractory to corticosteroids. Here, we report an autopsy case of pembrolizumab-induced pneumonitis that was transiently improved using infliximab. A 67-year-old male with advanced lung adenocarcinoma developed pneumonitis two weeks after a single dose of first-line pembrolizumab. The pneumonitis was refractory to corticosteroids, and the patient required mechanical ventilation. Addition of a single dose of infliximab rapidly improved the respiratory status and chest CT showed resolution of ground-glass opacities in the right upper and middle lobes. However, the patient died from re-exacerbation of pneumonitis 17 days after infliximab administration. The autopsy confirmed organizing phase diffuse alveolar damage in the right lower lobe, while the right upper lobe remained almost intact consistent with the CT findings, which is suggestive of the therapeutic effect of infliximab. The half-life of infliximab is 7-12 days, and a second dose of infliximab two weeks after the first dose is sometimes required for the treatment of gastrointestinal toxicity induced by anti-CTLA4 antibodies. Although the current guidelines do not recommend repeated administration of infliximab for immune-mediated pneumonitis, the present case suggests that repeated infliximab therapy may be beneficial in the treatment of immune-mediated pneumonitis.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Infliximab/administração & dosagem , Pneumonia/tratamento farmacológico , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Autopsia , Evolução Fatal , Humanos , Infliximab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
4.
Eur J Pharm Sci ; 137: 104993, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302214

RESUMO

Therapeutic protein medicines have transformed the treatment of blinding diseases (e.g. age-related macular degeneration, AMD) during the last 1-2 decades. Many blinding conditions such as AMD are chronic; and require multiple intravitreal injections over a long period to achieve a high and reproducible dose needed for clinical benefit. Prolonging the duration of action of ophthalmic drugs is critical to reduce the frequency of injections. Thermoresponsive hydrogels (e.g. N-isopropylacrylamide, NIPAAM) that collapse in physiological conditions can entrap and sustain the release of a therapeutic protein. However, most NIPAAM hydrogels are not biodegradable and often requires invasive surgery to remove the depot. Here, we report the preparation of a hydrogel derived from NIPAAM and acrylated hyaluronic acid (Ac-HA) as a biodegradable, macromolecular crosslinker. Ac-HA was prepared by the acrylation of hyaluronic acid (HA). Antibody (infliximab (INF), 5.0 mg/mL or bevacizumab (BEVA), 12.5 mg/mL), NIPAAM (0.35 mmol) and Ac-HA (2.0-10.0 mg/mL, 40.0-200.0 nmol) were first mixed prior to redox polymerisation to ensure maximal protein mixing and to shorten the burst release. Hydrogels with lower amounts of Ac-HA (2.0-4.0 mg/mL, 40.0-80.0 nmol) showed favourable lower critical solution temperature (LCST) values and injectability (27-29G) than higher amounts of Ac-HA (>4.0 mg/mL, >80.0 nmol). These hydrogels were further characterised (swelling ratio (SR), water retention (WR) and rheology). All hydrogels degraded in presence of bovine testes hyaluronidase (0-50 U/mL, 37 °C, 100 rpm). Release studies of BEVA-loaded hydrogels were investigated in vitro using the PK-Eye™ model, which estimates the human clearance times of proteins from the back of the eye. Phosphate buffered saline (PBS, pH 7.4, 37 °C) was used rather than simulated vitreous to more effectively map trends between the formulations. A zero-order release profile was observed between days 5 to 50 with 43.3 ±â€¯9.5% protein released at day 50. Determining protein binding and functionality from a formulation is crucial to determine the optimal formulation prior to more detailed studies that might be necessary. BEVA showed binding to human vascular growth endothelial factor (VEGF165) throughout the study (two months) while still maintaining a therapeutic dose (123.5 ±â€¯45.6 ng) in the posterior cavity of the PK-Eye™ model. These encouraging results suggest that extended release of proteins in the vitreous can be achieved using injectable hydrogels derived from NIPAAM and HA.


Assuntos
Acrilamidas/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Bevacizumab/administração & dosagem , Ácido Hialurônico/administração & dosagem , Hidrogéis/administração & dosagem , Infliximab/administração & dosagem , Acrilamidas/química , Anti-Inflamatórios/química , Bevacizumab/química , Olho/metabolismo , Humanos , Ácido Hialurônico/química , Hialuronoglucosaminidase/química , Hidrogéis/química , Infliximab/química , Injeções Intravítreas , Modelos Biológicos
5.
Expert Rev Pharmacoecon Outcomes Res ; 19(5): 537-549, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31340686

RESUMO

Introduction: Early biological treatment of rheumatoid arthritis (RA) may reverse the autoimmune response in some patients resulting in favorable long-term outcomes. Although the cost-effectiveness of this strategy has been questioned, biosimilar entries warrant the revision of clinical and pharmaco-economic evidence. Areas covered: We conducted a systematic review of randomized controlled trials (RCTs) published up to 24 May 2018 in Pubmed, EMBASE and Cochrane CENTRAL, comparing infliximab with non-biological therapy in patients with RA naïve to methotrexate. We performed meta-analyses for efficacy outcomes at month 6 and years 1 and 2. Six RCTs were identified, involving 1832 patients. At month 6 ACR70 response and remission, and at year 1 ACR20/ACR70 responses and remission were improved significantly with first-line infliximab versus control. The differences were not significant at year 2. We reviewed cost-utility studies, up to 31 October 2018 in PubMed, Cochrane CENTRAL and the CRD HTA databases. Four studies indicated that first-line use of originator infliximab calculated at 2005-2008 prices was not cost-effective. Expert opinion: We demonstrated the efficacy benefits of first-line infliximab therapy up to 1 year in methotrexate-naïve RA. We highlighted the need for standardized reporting of outcomes and conducting cost-effectiveness analyses of first-line biosimilar therapy in RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Infliximab/administração & dosagem , Antirreumáticos/economia , Artrite Reumatoide/economia , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/economia , Análise Custo-Benefício , Farmacoeconomia , Humanos , Infliximab/economia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
6.
Drugs ; 79(10): 1053-1063, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31183768

RESUMO

The inflammatory bowel diseases commonly affect individuals during their peak reproductive years. Patients are often concerned about the impact of medical therapies on their ability to conceive, effect on the fetus, as well as the ability to breastfeed, which has led to poor medical adherence during pregnancy. However, most medications are safe, and discontinuation may lead to active disease, which is associated with adverse materno-fetal outcomes. The anti-TNF biologic therapies, infliximab and adalimumab have been extensively studied in the context of pregnancy. They are actively transferred to the placenta during the second and third trimesters; these have not been associated with an increased rate of congenital abnormalities or fetal death. The minimal amounts of drug that are transferred to breast milk are proteolyzed by the infant's digestive system with no reported short- or long-term adverse effects. There is a paucity of clinical data for the other approved anti-TNF agents or newer anti-integrin (vedolizumab) and anti-interleukin (ustekinumab) therapies used in the management of inflammatory bowel disease; however, no significant safety signals have been documented thus far. The new oral small molecule therapy, tofacitinib is teratogenic in animal models and is contra-indicated in patients attempting pregnancy. It is important that patients, as well as physicians managing patients with these conditions, be aware of the impact of these medical therapies during pregnancy.


Assuntos
Adalimumab/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/administração & dosagem , Ustekinumab/administração & dosagem , Adalimumab/efeitos adversos , Administração Oral , Anticorpos Monoclonais Humanizados/efeitos adversos , Aleitamento Materno , Desenvolvimento Infantil/efeitos dos fármacos , Feminino , Humanos , Recém-Nascido , Infliximab/efeitos adversos , Leite Humano/química , Leite Humano/metabolismo , Gravidez , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/efeitos adversos
7.
Pediatrics ; 143(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31048414

RESUMO

BACKGROUND: Coronary artery aneurysms (CAA) are a serious complication of Kawasaki disease. Treatment with intravenous immunoglobulin (IVIg) within 10 days of fever onset reduces the risk of CAA from 25% to <5%. Corticosteroids and infliximab are often used in high-risk patients or those with CAA at diagnosis, but there are no data on their longer-term impact on CAA. METHODS: Retrospective multicenter study including children who had CAA with a z score ≥2.5 and <10 at time of diagnosis and who received primary therapy with IVIg alone or in combination with either corticosteroids or infliximab within 10 days of onset of fever. RESULTS: Of 121 children, with a median age of 2.8 (range 0.1-15.5) years, 30 (25%) received primary therapy with corticosteroids and IVIg, 58 (48%) received primary therapy with infliximab and IVIg, and 33 (27%) received primary therapy with IVIg only. Median coronary z scores at the time of diagnosis did not differ among treatment groups (P = .39). Primary treatment intensification with either corticosteroids or infliximab were independent protective factors against progression of coronary size on follow-up (coefficient: -1.31 [95% confidence interval: -2.33 to -0.29]; coefficient: -1.07 [95% confidence interval: -1.95 to -0.19], respectively). CONCLUSIONS: Among a high-risk group of patients with Kawasaki disease with CAA on baseline echocardiography, those treated with corticosteroids or infliximab in addition to IVIg had less progression in CAA size compared with those treated with IVIg alone. Prospective randomized trials are needed to determine the best adjunctive treatment of patients who present with CAA.


Assuntos
Aneurisma Coronário/tratamento farmacológico , Aneurisma Coronário/epidemiologia , Imunoglobulinas Intravenosas/administração & dosagem , Infliximab/administração & dosagem , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Adolescente , Antirreumáticos/administração & dosagem , Criança , Pré-Escolar , Aneurisma Coronário/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
8.
Int J Pharm ; 565: 533-542, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31085256

RESUMO

In this study we examined the potential of novel biodegradable polymers of polyesterurethane (PU), and its PEGylated (PU-PEG) form as nanocarriers of Infliximab (INF), to treat inflammation in an in-vitro epithelial model. Nanoparticles (NPs) formulated were of average size of 200-287 nm. INF loading of NPs (INF-NPs) resulted in an increase in size and zeta potential. No cytotoxicity was observed for any of the NPs. Cellular interaction and uptake of PU NPs were similar compared with polycaprolactone (PCL) NPs and significantly higher to Poly(lactic-co-glycolic) acid (PLGA) NPs. Cellular interaction was higher for corresponding PEG-NPs. INF-PU and INF-PU-PEG NPs showed a rapid rate and extent of recovery of the epithelial barrier function in inflamed Caco-2 cell monolayers and decreased cytokine levels in inflamed monocytes. Results obtained in this study are promising and the potential of PU and PU-PEG NPs for drug delivery and targeting to treat gastrointestinal inflammation warrants further investigation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Portadores de Fármacos/administração & dosagem , Infliximab/administração & dosagem , Nanopartículas/administração & dosagem , Poliuretanos/administração & dosagem , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucina-8/imunologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fator de Necrose Tumoral alfa/imunologia
9.
J Am Acad Dermatol ; 81(3): 702-708, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31095972

RESUMO

BACKGROUND: Few data exist to guide infliximab dosing in hidradenitis suppurativa (HS). OBJECTIVES: To determine optimal infliximab dosing for patients with HS based on treatment response and achievement of stable dosing. METHODS: Retrospective cohort study of 52 patients with HS treated with infliximab. Primary outcome was achievement of stable dosing regimen for at least 8 weeks. Secondary outcomes were time to discontinuation, time to titration, changes to inflammatory markers, and clinical response. RESULTS: Thirty-five patients (67%) achieved stable dosing, most at a schedule of 10 mg/kg every 6 or 8 weeks. At 1 year from initiation, most patients (64%) required dose escalation. Patients tolerated infliximab well and achieved significant improvements in abscess and nodule count, draining sinuses, and erythrocyte sedimentation rate. LIMITATIONS: Retrospective nature and lack of HS clinical response data for many patients. CONCLUSIONS: Infliximab 10 mg/kg every 6 or 8 weeks may be a reasonable starting dosage for most patients.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Hidradenite Supurativa/tratamento farmacológico , Infliximab/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hidradenite Supurativa/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
10.
Ir Med J ; 3(112): 902, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-31124350

RESUMO

Aim To report the first case of cardiac tamponade related to Infliximab induction therapy in an Ulcerative Colitis patient. Methods Review of published case reports. Results This complication was likely due to a type 3 hypersensitivity immune-complex reaction resulting in a reactive pericardial effusion Discussion Though rare, this case demonstrates how autoimmune reaction to anti-TNF𝛼 therapy can initially mimic infection, as our patient presented with tachycardia, hypotension, raised inflammatory and infective markers and fever.


Assuntos
Tamponamento Cardíaco/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Infliximab/efeitos adversos , Autoimunidade , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/imunologia , Tamponamento Cardíaco/terapia , Colite Ulcerativa/imunologia , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/imunologia , Humanos , Infliximab/administração & dosagem , Infliximab/imunologia , Pessoa de Meia-Idade , Derrame Pericárdico/induzido quimicamente , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/imunologia , Derrame Pericárdico/terapia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
11.
World J Gastroenterol ; 25(18): 2240-2250, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31143074

RESUMO

BACKGROUND: When opportunistic infections occur, patients with inflammatory bowel disease (IBD) commonly display a significantly increased rate of morbidity and mortality. With increasing use of immunosuppressive agents and biological agents, opportunistic infections are becoming a hot topic in the perspective of drug safety in IBD patients. Despite the well-established role of opportunistic infections in the prognosis of IBD patients, there are few epidemiological data investigating the incidence of opportunis-tic infections in IBD patients in China. Besides, the risk factors for opportunistic infection in Chinese IBD patients remain unclear. AIM: To predict the incidence of opportunistic infections related to IBD in China, and explore the risk factors for opportunistic infections. METHODS: A single-center, prospective study of IBD patients was conducted. The patients were followed for up to 12 mo to calculate the incidence of infections. For each infected IBD patient, two non-infected IBD patients were selected as controls. A conditional logistic regression analysis was used to assess associations between putative risk factors and opportunistic infections, which are represented as odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Seventy (28.11%) out of 249 IBD patients developed opportunistic infections. Clostridium difficile infections and respiratory syncytial virus infections were found in 24 and 16 patients, respectively. In a univariate analysis, factors such as the severity of IBD, use of an immunosuppressant or immunosuppressants, high levels of fecal calprotectin, and C-reactive protein or erythrocyte sedimentation rate were individually related to a significantly increased risk of opportunistic infection. Multivariate analysis indicated that the use of any immunosuppressant yielded an OR of 3.247 (95%CI: 1.128-9.341), whereas the use of any two immunosuppressants yielded an OR of 6.457 (95%CI: 1.726-24.152) for opportunistic infection. Interestingly, when immunosuppressants were used in combination with infliximab (IFX) or 5-aminosalicylic acid, a significantly increased risk of opportunistic infection was also observed. The relative risk of opportunistic infection was greatest in IBD patients with severe disease activity (OR = 9.090; 95%CI: 1.532-53.941, relative to the remission stage). However, the use of IFX alone did not increase the risk of opportunistic infection. CONCLUSION: Factors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients. The use of IFX alone does not increase the risk of opportunistic infection.


Assuntos
Doenças Inflamatórias Intestinais/complicações , Infecções Oportunistas/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , China/epidemiologia , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Fezes/química , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Incidência , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Complexo Antígeno L1 Leucocitário/análise , Masculino , Mesalamina/administração & dosagem , Mesalamina/efeitos adversos , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Infecções Oportunistas/complicações , Infecções Oportunistas/imunologia , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
12.
PLoS One ; 14(5): e0216746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31145730

RESUMO

OBJECTIVES: To compare drug survival in patients with axial spondyloarthritis treated with different TNF inhibitors in standard dosage. METHODS: Patients fulfilling the Assessment in SpondyloArthritis international Society classification criteria for axial spondyloarthritis in the Swiss Clinical Quality Management cohort were included in this study if a first TNF inhibitor on standard dosage was started after recruitment and if a baseline visit was available. Drug maintenance up to drug discontinuation or dose escalation was compared between TNF inhibitors with multiple adjusted Cox proportional hazards models and multiple imputation for missing baseline covariate data. RESULTS: A total of 966 patients were included (adalimumab 344, etanercept 237, golimumab 214, infliximab 171). Patients on certolizumab (n = 18) were excluded. Patients starting golimumab had lower disease activity as well as better physical function and quality of life in comparison to patients starting another drug. A higher proportion of patients starting infliximab had a history of extra-articular manifestations. Drug dosage was more often escalated during follow-up in patients treated with infliximab than with subcutaneously administered agents. However, no significant differences in time up to drug discontinuation or dose escalation were observed in multiple adjusted analyses if treatment was initiated after 2009, when all 4 TNF inhibitors were available: hazard ratio for infliximab versus etanercept 1.16 (95% confidence interval 0.80; 1.67), p = 0.44, for golimumab versus etanercept 0.80 (0.58; 1.10), p = 0.17 and for adalimumab versus etanercept 0.93 (0.69; 1.26), p = 0.66. CONCLUSION: In axial spondyloarthritis, drug survival with standard doses of different TNF inhibitors is comparable.


Assuntos
Adalimumab/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Etanercepte/administração & dosagem , Infliximab/administração & dosagem , Espondilartrite/tratamento farmacológico , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Antirreumáticos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , /administração & dosagem
13.
BMJ Case Rep ; 12(5)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126928

RESUMO

Relapsing polychondritis (RP) is a rare progressive and destructive multisystem disorder characterised by recurrent inflammation of cartilaginous structures. It is a rare disease in paediatrics compared with adults. In children, the diagnosis is either delayed or overlooked due to low incidence. Auricular chondritis has been described in more than half of paediatric cases with RP. However, isolated auricular chondritis has not been reported as the only presentation of pediatric-onset RP. We described a lad who presented with isolated auricular chondritis, which is refractory to conventional treatment, including glucocorticoids and methotrexate as steroid-sparing agent. Remission of his disease's relapses was sustained with infliximab. Limited auricular involvement as a presenting feature of RP in the absence of systemic association is very rare in children. We describe a case of successful use of infliximab on limited auricular chondritis disease.


Assuntos
Policondrite Recidivante/diagnóstico , Adolescente , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Diagnóstico Diferencial , Pavilhão Auricular , Humanos , Infliximab/administração & dosagem , Infliximab/uso terapêutico , Masculino , Policondrite Recidivante/tratamento farmacológico , Policondrite Recidivante/patologia
16.
Tidsskr Nor Laegeforen ; 139(7)2019 Apr 09.
Artigo em Norueguês, Inglês | MEDLINE | ID: mdl-30969044

RESUMO

BACKGROUND: Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, has a predilection for the upper airways, lungs and kidneys. However, any other organ can be affected. Although cutaneous lesions are common, they have only rarely been reported as a primary manifestation of the disease. CASE PRESENTATION: We present a case of a teenage boy with pyoderma gangrenosum-like ulcerations of the neck and face. Anti-neutrophil cytoplasmic antibody with antigen specificity for proteinase 3 (PR3-ANCA) was detected. In the absence of other symptoms and organ manifestations, the ulcerations were still considered to be pyoderma gangrenosum. The ulcers started to heal during treatment with corticosteroids and infliximab. One month later the patient developed sinusitis, and eventually lost vision in his left eye. The diagnosis was changed to GPA and he started treatment with methylprednisolone, rituximab and cyclophosphamide with good response on vision, sinusitis and ulcerations. INTERPRETATION: Recognition of this rare skin presentation of GPA is essential, to prevent delays in diagnosis and treatment that can lead to organ damage.


Assuntos
Face/patologia , Granulomatose com Poliangiite , Pescoço/patologia , Úlcera Cutânea/etiologia , Adolescente , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Diagnóstico Diferencial , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/patologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Infliximab/administração & dosagem , Infliximab/uso terapêutico , Masculino , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Pioderma Gangrenoso/diagnóstico , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Úlcera Cutânea/tratamento farmacológico , Úlcera Cutânea/patologia
17.
Dig Dis Sci ; 64(7): 1952-1958, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30815825

RESUMO

BACKGROUND: Tumor necrosis factor antagonists (TNFs) are effective for moderate-severe Crohn's disease (CD). Approximately one-third of patients have primary-nonresponse to TNFs, which is reported to predict worse response to subsequent TNF therapy. However, this is based on treatment with subcutaneously (SC) administered, fixed-dose TNFs after failure of intravenously (IV) administered, weight-based TNFs. No study has specifically assessed the clinical and endoscopic effectiveness of IV TNFs following primary-nonresponse to SC TNFs. We hypothesize that IV, weight-based TNF dosing offers advantages over SC, fixed-dose TNFs and may be effective despite primary-nonresponse to previous SC fixed-dose TNFs. METHODS: This retrospective cohort study identified patients with moderate-severe CD with primary-nonresponse to one or more SC TNFs who subsequently received the IV TNF, infliximab for ≥ 12 weeks. We described baseline characteristics, and clinical, endoscopic and biochemical response to therapy. RESULTS: Key characteristics of 17 patients are described in Table 1. After ≥ 12 weeks of infliximab, 11 of 15 (73.3%) patients with clinical data reported clinical response and remission. Of 11 patients with endoscopic data, restaging colonoscopy revealed mucosal improvement in seven (63.6%) patients. Of these, five (45.5%) had endoscopic remission and three (27.3%) had mucosal healing. Table 1 Baseline characteristics of CD patients with primary-nonresponse to subcutaneous (SC) tumor necrosis antagonists (TNF), subsequently treated with intravenous (IV) TNF therapy Characteristics N 17 Mean age, years (range) 37.5 (18-67) Mean BMI, kg/m2 (range) 26.6 (17.8-40.6) Mean albumin prior to infliximab, g/dL (range) RR: 3.5-5.2 g/dL 3.57 (2.5-4.2) Female sex [n (%)] 7 (41.2) Tobacco use [n (%)]  Never 15 (88.2)  Former 1 (5.88)  Current 1 (5.88) Age at diagnosis [n (%)]  Less than 17 2 (11.8)  17-40 11 (64.7)  Over 40 4 (23.5) Mean disease duration, yrs (range) 7.76 (1-24) Disease extent [n (%)]  Ileal 2 (11.8)  Colonic 5 (29.4)  Ileocolonic 10 (64.7) Disease behavior [n (%)]  Nonstenosing, nonpenetrating 10 (58.8)  Stenosing 3 (17.6)  Penetrating 2 (11.8)  Stenosing and penetrating 2 (11.8) History of gastrointestinal surgery [n (%)] 4 (23.5)  Ileocecal resection (n) 2  Hemicolectomy (n) 2 Prior therapy [n (%)]  IV corticosteroids 3 (17.6)  Oral corticosteroids 14 (82.4)  5-ASA 12 (70.6)  Thiopurine 14 (82.4)  Methotrexate 10 (58.8) Prior biologic therapy  Adalimumab only 12 (70.6)  Certolizumab pegol only 2 (11.8)  Adalimumab and certolizumab pegol 2 (11.8)  Adalimumab, certolizumab pegol and golimumab 1 (5.88) Dose escalation of prior SC TNF [n (%)]  Adalimumab 9 (52.9)  Certolizumab pegol 0 (0.0)  Golimumab 0 (0.0) During infliximab, concomitant therapy [n (%)]  Immunomodulator 13 (76.5)  Corticosteroid 5 (29.4) CONCLUSIONS: Patients with moderate-severe CD with prior primary-nonresponse to SC, fixed-dose TNFs, subsequently treated with IV, weight-based TNF have high rates of clinical and endoscopic response and remission. Therefore, despite primary-nonresponse to SC TNFs, patients may benefit from IV TNF therapy and may not require a change to a different class of biologic therapy.


Assuntos
Produtos Biológicos/administração & dosagem , Doença de Crohn/tratamento farmacológico , Infliximab/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Intravenosa , Adolescente , Adulto , Idoso , Produtos Biológicos/efeitos adversos , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Humanos , Infliximab/efeitos adversos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia , Cicatrização/efeitos dos fármacos , Adulto Jovem
18.
Expert Opin Drug Metab Toxicol ; 15(5): 399-406, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30892105

RESUMO

INTRODUCTION: The incidence and prevalence of Crohn's disease are increasing causing a significant disease burden. Therapeutic drug monitoring (TDM) is advocated as a promising tool for personalized or individual-tailored therapy strategies and has been welcomed as a new means to improve current therapy strategies. Nevertheless, pharmacokinetic-based TDM has limitations, and straightforward target concentrations for most therapies are lacking. Areas covered: In the following concise review of literature, key insights of TDM in thiopurine, methotrexate, anti-TNF, vedolizumab and ustekinumab therapy for Crohn's disease are being described. Expert opinion: Therapeutic drug monitoring may, up till now, be helpful to adjust thiopurine and infliximab therapy, primarily in a reactive setting, in case of inefficacy and of occurrence of adverse event. With this restricted application, the goal of individualized therapy based on TDM has not yet been achieved.


Assuntos
Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/farmacocinética , Humanos , Infliximab/administração & dosagem , Infliximab/farmacocinética , Purinas/administração & dosagem , Purinas/farmacocinética
19.
J Crohns Colitis ; 13(8): 982-989, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30715240

RESUMO

BACKGROUND: Infliximab pharmacokinetics in steroid-refractory [SR] ulcerative colitis [UC] suggest a need for higher dosing, but data concerning efficacy of intensification in this setting are lacking in children and inconsistent overall. METHODS: Paediatric patients [N = 125] treated with infliximab for SR or steroid-dependent UC were retrospectively reviewed. Outcomes [clinical response and remission, colectomy, mucosal healing, safety] with standard vs intensified induction [mean induction dose ≥7 mg/kg or interval ≤5 weeks between doses 1 and 3] were compared. RESULTS: Among 125 patients [median age 14 years, median UC duration 0.7 years, 74 SR], 73 [58%] received standard induction and 52 [42%] received intensified induction. Overall, 73 [58%] achieved remission (judged by physician global assessment [PGA] and paediatric UC activity index [PUCAI]≤10]. Among patients in remission, 7 [10%] experienced secondary loss of response by a median of 0.7 [IQR 0.4-1.0] years. Of the 74 SR patients, 17 [23%] underwent colectomy, and of the 51 steroid-dependent patients, 12 [24%] underwent colectomy. Intensified induction in SR patients was associated with a higher chance of remission (hazard ratio [HR] 3.2, p = 0.02) and a lower chance of colectomy [HR 0.4, p = 0.05], but did not improve outcomes in steroid-dependent patients. During follow-up, 46/73 [63%] patients in remission had regimen individualization, with similar rates of return to standard dosing after 1 year between those with initial intensified or standard induction. Follow-up endoscopy, performed in 35/73 patients in remission, demonstrated mucosal healing for 66%. Adverse events were rare, despite use of intensified regimens. CONCLUSIONS: These data suggest a benefit from intensified infliximab induction specifically among children with steroid-refractory UC. Prospective studies comparing dosing regimens and incorporating therapeutic drug monitoring should be undertaken.


Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa , Monitoramento de Medicamentos/métodos , Infliximab , Indução de Remissão/métodos , Adolescente , Canadá/epidemiologia , Criança , Colectomia/métodos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/imunologia , Endoscopia Gastrointestinal/métodos , Feminino , Seguimentos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Mucosa Intestinal/patologia , Masculino , Gravidade do Paciente , Resultado do Tratamento
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