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1.
Hum Exp Toxicol ; 38(11): 1275-1282, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31378095

RESUMO

Carbon tetrachloride (CCL4) is often employed in the production of chlorofluorocarbons, petroleum refining, oil and rubber processing, and laboratory applications. Oral, subcutaneous, and inhalation exposure to CCL4 in animal studies have been shown to be capable of leading to various types of cancer (benign and malignant, liver, breast, and adrenal gland tumors). The present study also evaluated the protective role of infliximab (INF) against the deleterious effects of CCL4 on the intestinal system. Twenty-four male Sprague-Dawley rats were randomly assigned into three groups, control (n = 8), CCL4 (n = 8), and CCL4 + INF (n = 8). The control group received 1 mL isotonic saline solution only via intraperitoneal (i.p.) injection. The CCL4 group received a single i.p. dose of 2 mL/kg CCL4. The CCL4 + INF group received a single i.p. dose of 7 mg/kg INF followed 24 h later by a single dose of 2 mL/kg CCL4. All rats were euthanized 2 days following drug administration. CCL4 group samples also exhibited diffuse loss of enterocytes, vascular congestion, neutrophil infiltration, an extension of the subepithelial space and significant epithelial lifting along the length of the villi with a few denuded villous tips. In addition, CCL4 treatment increased intestinal malondialdehyde (MDA) level and caspase-3 positivity. On the other hand, INF decreased MDA levels, caspase-3 positivity, and loss of villous. Our findings suggest that CCL4 appears to exert a highly deleterious effect on the intestinal mucosa. On the other hand, INF is effective in preventing this CCL4-induced intestinal injury by reducing oxidative stress and apoptosis.


Assuntos
Infliximab/uso terapêutico , Enteropatias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono , Infliximab/farmacologia , Enteropatias/induzido quimicamente , Enteropatias/metabolismo , Enteropatias/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
2.
BMC Cancer ; 19(1): 658, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272418

RESUMO

BACKGROUND: Expression of Bcr-Abl in hematopoietic stem cells is sufficient to cause chronic myeloid leukemia (CML) and tyrosine kinase inhibitors (TKI) induce molecular remission in the majority of CML patients. However, the disease driving stem cell population is not fully targeted by TKI therapy, and leukemic stem cells (LSC) capable of re-inducing the disease can persist. Single-cell RNA-sequencing technology recently identified an enriched inflammatory gene signature with TNFα and TGFß being activated in TKI persisting quiescent LSC. Here, we studied the effects of human TNFα antibody infliximab (IFX), which has been shown to induce anti-inflammatory effects in mice, combined with TKI treatment on LSC function. METHODS: We first performed GSEA-pathway analysis using our microarray data of murine LSK cells (lin-; Sca-1+; c-kit+) from the SCLtTA/Bcr-Abl CML transgenic mouse model. Bcr-Abl positive cell lines were generated by retroviral transduction. Clonogenic potential was assessed by CFU (colony forming unit). CML mice were treated with nilotinib or nilotinib plus infliximab, and serial transplantation experiments were performed. RESULTS: Likewise to human CML, TNFα signaling was specifically active in murine CML stem cells, and ectopic expression of Bcr-Abl in murine and human progenitor cell lines induced TNFα expression. In vitro exposure to human (IFX) or murine (MP6-XT22) TNFα antibody reduced clonogenic growth of CML cells. Interestingly, TNFα antibody treatment enhanced TKI-induced effects on immature cells in vitro. Additionally, in transplant and serial transplant experiments, using our transgenic CML mouse model, we could subsequently show that IFX therapy boosted TKI-induced effects and further reduced the proportion of malignant stem cells in vivo. CONCLUSION: TNFα signaling is induced in CML stem cells, and anti-inflammatory therapy enhances TKI-induced decline of LSC, confirming that successful targeting of persisting CML stem cells can be enhanced by addressing their malignant microenvironment simultaneously.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infliximab/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Infliximab/farmacologia , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução Genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Dermatol ; 46(9): 808-811, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31290564

RESUMO

Disseminated granuloma annulare (GA) is a rare granulomatous dermatitis of unknown etiology. Treatment is often challenging and lack of a uniformly effective treatment, adds to the disease morbidity. Tumor necrosis factor (TNF)-α is an important cytokine in granuloma formation and previous reports have shown improvement of disseminated GA with anti-TNF-α therapy. Nevertheless, the underlying mechanism of actions of TNF-α inhibitors in GA remains unclear. Our aim was to evaluate alterations in the inflammatory infiltrate in a patient who experienced complete clearance of GA after treatment with infliximab. A skin biopsy was obtained before and 24 weeks after treatment with infliximab 5 mg/kg at weeks 0, 2, 6, 14 and 24. Immunohistochemical stains were performed in pre- and post-treatment biopsy specimens using CD1a, CD4, CD8, CD11c, CD32, CD68, CD69, CD163, CD183 and human leukocyte antigen (HLA)-DR to characterize alterations of the infiltrates. Parallel with clinical improvement, we observed a marked decrease in myeloid (CD11c) dendritic cells, different macrophage subsets (CD68, CD32, CD163) and T cells. In addition, a marked reduction of activation markers (HLA-DR, CD69) and CD183+ (CXCR3) cells was observed in post-treatment biopsy specimens. In conclusion, the clinical improvement of disseminated GA by infliximab is paralleled by inhibition of activated myeloid dendritic cells, different macrophage subsets and type 1 T cells.


Assuntos
Células Dendríticas/efeitos dos fármacos , Fármacos Dermatológicos/farmacologia , Granuloma Anular/tratamento farmacológico , Infliximab/farmacologia , Macrófagos/efeitos dos fármacos , Idoso , Biópsia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fármacos Dermatológicos/uso terapêutico , Granuloma Anular/imunologia , Granuloma Anular/patologia , Humanos , Infliximab/uso terapêutico , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Pele/citologia , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
4.
Ecotoxicol Environ Saf ; 182: 109398, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31276887

RESUMO

Cadmium(Cd) is a serious environmental and occupational contaminant that represents a serious health hazard to humans and other animals. Reproductive health problems have been reported in men exposed to Cd. Testicular damage is one of the deleterious effects due to Cd exposure. Cd-induced testicular toxicity is mediated through oxidative stress, inflammation, testosterone inhibition and apoptosis. Thus, the present study was performed to assess the possible protective role of infliximab (IFX), anti-TNFα agent, against Cd-induced testicular damage and spermiotoxicity in rats. The rats were randomly allotted into six experimental groups: control, Cd sulphate treated, Cd sulphate treated with infliximab (5 mg/kg), Cd sulphate with infliximab (7 mg/kg), infliximab alone (5 mg/kg), and infliximab alone (7 mg/kg). The control group received saline. To induce testicular damage, Cd sulphate (1.5 mg/100 gm body weight/day) was dissolved in normal saline and orally administrated for 3 consecutive weeks. The rats in infliximab-treated groups were given a weekly dose of 5 mg/kg/week or 7 mg/kg/week of infliximab intraperitoneally. In the current study Cd exposure reduced sperm count, markers of testicular function, sperm motility as well as gene expression of testicular 3ß-HSD and 17ß-HSD and serum testosterone level. Additionally, it increased testicular oxidative stress, inflammatory and apoptotic markers. The histopathologic studies supported the biochemical findings. Treatment with infliximab significantly attenuated Cd-induced injury verified by the restoration of testicular architecture, enhancement of steroidogenesis, preservation of spermatogenesis, modulation of the inflammatory reaction along with suppression of oxidative stress and apoptosis. It was concluded that infliximab, through its antioxidant, anti-inflammatory and anti-apoptotic effects, represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of Cd.


Assuntos
Antioxidantes/metabolismo , Cádmio/toxicidade , Infliximab/farmacologia , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Inflamação , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testosterona/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
PLoS Comput Biol ; 15(5): e1006933, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31071076

RESUMO

Anti-TNF agents have been in the first line of treatment of various inflammatory diseases such as Rheumatoid Arthritis and Crohn's Disease, with a number of different biologics being currently in use. A detailed analysis of their effect at transcriptome level has nevertheless been lacking. We herein present a concise analysis of an extended transcriptomics profiling of four different anti-TNF biologics upon treatment of the established hTNFTg (Tg197) mouse model of spontaneous inflammatory polyarthritis. We implement a series of computational analyses that include clustering of differentially expressed genes, functional analysis and random forest classification. Taking advantage of our detailed sample structure, we devise metrics of treatment efficiency that take into account changes in gene expression compared to both the healthy and the diseased state. Our results suggest considerable variability in the capacity of different biologics to modulate gene expression that can be attributed to treatment-specific functional pathways and differential preferences to restore over- or under-expressed genes. Early intervention appears to manage inflammation in a more efficient way but is accompanied by increased effects on a number of genes that are seemingly unrelated to the disease. Administration at an early stage is also lacking in capacity to restore healthy expression levels of under-expressed genes. We record quantifiable differences among anti-TNF biologics in their efficiency to modulate over-expressed genes related to immune and inflammatory pathways. More importantly, we find a subset of the tested substances to have quantitative advantages in addressing deregulation of under-expressed genes involved in pathways related to known RA comorbidities. Our study shows the potential of transcriptomic analyses to identify comprehensive and distinct treatment-specific gene signatures combining disease-related and unrelated genes and proposes a generalized framework for the assessment of drug efficacy, the search of biosimilars and the evaluation of the efficacy of TNF small molecule inhibitors.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite/genética , Perfilação da Expressão Gênica/métodos , Adalimumab/farmacologia , Animais , Artrite/tratamento farmacológico , Medicamentos Biossimilares , Certolizumab Pegol/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/imunologia , Infliximab/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transcriptoma/genética , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
8.
World J Gastroenterol ; 25(14): 1764-1774, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011260

RESUMO

BACKGROUND: Identifying predictors of therapeutic response is the cornerstone of personalized medicine. AIM: To identify predictors of long-term mucosal healing (MH) in patients with Crohn's disease (CD) treated with tumor necrosis factor α (TNF-α) inhibitors. METHODS: Prospective single center study. Consecutive patients with clinically active CD requiring treatment with a TNF-α inhibitor were included. A baseline segmental CD Endoscopic Index of Severity (CDEIS) ≥ 10 in at least one segment or the presence of ulcerations were required for inclusion. Clinical, biological and endoscopic data were obtained at baseline, weeks 14 and 46. Endoscopic response (ER) was defined as a decrease ≥ 50% from baseline CDEIS and MH as partial CDEIS ≤ 5 in all segments. RESULTS: Of 62 patients were included. At baseline, median CD Activity Index and CDEIS were 201 and 6.7, respectively with a significant reduction after one year of treatment (53 and 3.0 respectively, P < 0.001). At week 14, 56% of patients achieved ER and 34% MH. At week 46, the corresponding percentages were 52% and 44%. Baseline disease characteristics or biomarkers did not predict MH. A decrease from baseline CDEIS at week 14 of at least 80% was the best predictor of MH at week 46 (59% sensitivity and 91% specificity; area under the curve = 0.778). CONCLUSION: Clinical and biomarker data are not useful predictors of response to TNF-α inhibitors in CD, whereas ER to induction therapy, defined as 80% reduction in global CDEIS, is a robust predictor of long-term MH. Achievement of this endoscopic endpoint may be considered as a therapeutic target for anti-TNF-α therapy.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Mucosa Intestinal/diagnóstico por imagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Adulto , Idoso , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/patologia , Colonoscopia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Quimioterapia Combinada/métodos , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Íleo/diagnóstico por imagem , Íleo/efeitos dos fármacos , Íleo/patologia , Infliximab/farmacologia , Infliximab/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Drug Des Devel Ther ; 13: 791-805, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880912

RESUMO

Background: Infliximab (Remicade), a chimeric monoclonal antibody against human TNFα, will inevitably face competition from biosimilar products, because of its effectiveness in autoimmune diseases and rapidly increasing market demand. According to guidelines for biosimilar development, the "biosimilar-expression system" may differ from that of the innovator, but more appropriate studies should be carried out to demonstrate the comparability between biosimilar and innovator. CMAB008 is an infliximab biosimilar candidate developed by the State Key Laboratory of Antibody Medicine and Targeted Therapy of China. Infliximab was expressed in SP2/0 cells, while CMAB008 was produced in a CHO-expression system. Methods: In this study, infliximab and CMAB008 were compared on physicochemical and biological characterizations, including protein content, activity, physiochemical integrity, impurities, additives, and immunogenicity. Results: The results showed that they were highly similar and comparable, except some differences in glycosylation. As glycosylation profiles can influence immunogenicity and occurrence of allergy or other adverse reactions of antibody therapeutics, primary tolerability and pharmacokinetics of CMAB008 were evaluated. In the phase I clinical trial, plasma concentration of CMAB008 and antidrug antibodies were also measured using ELISA and bridging ELISA, respectively. CMAB008 exhibited favorable clinical tolerability, no adverse events in the 3 mg/kg single-dose group (recommended therapeutic dosage), and no serious adverse events in the multiple-dose group. Also, no injection-site reactions were observed in the experiment. Conclusion: In summary, CMAB008 might have the potential to be an effective drug compared with infliximab.


Assuntos
Infliximab/química , Infliximab/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Química Física , Voluntários Saudáveis , Humanos , Infliximab/efeitos adversos , Infliximab/farmacocinética , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos , Modelos Animais
11.
Immunol Invest ; 48(5): 441-450, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30569777

RESUMO

Anti-TNF antibodies are major therapeutics for rheumatoid arthritis and have been approved for marketing in many countries. Antibody-dependent cellular cytotoxicity (ADCC) is considered to be a potential mechanism of action of anti-TNF antibodies, since some anti-TNF antibodies have been confirmed to induce cytotoxic effects on TNF-producing cells via ADCC and complement-dependent cytotoxicity (CDC) in in vitro experiments. In this study, we established a new stable effector cell line expressing human FcγRIIIa, CD16:KHYG-1, and compared the performance of this cell line with that of peripheral blood mononuclear cells (PBMCs) in ADCC assays against CHO-derived target cells expressing protease-sensitive pro-TNF. Although an inhibitory effect of soluble TNF released from pro-TNF expressing cells on ADCC activity was seen, clear dose-responsive ADCC activities were observed even in the presence or absence of TNF-α converting enzyme (TACE) inhibitor. However, significant differences in the ADCC activities in the presence or absence of TACE inhibitor were only noted when CD16:KHYG-1 cells were used as the effector cells. Our findings indicate that soluble TNF may influence ADCC activity of anti-TNF antibody. Moreover, the fact that the influence was able to be detected only in the case using stable effector cell also suggests that the stable effector cell established this time enable highly accurate ADCC measurement.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Infliximab/uso terapêutico , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17/metabolismo , Animais , Citotoxicidade Celular Dependente de Anticorpos , Células CHO , Linhagem Celular , Cricetulus , Dipeptídeos/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Infliximab/farmacologia , Células Matadoras Naturais/patologia , Receptores de IgG/genética , Receptores de IgG/metabolismo , Transgenes/genética , Fator de Necrose Tumoral alfa/imunologia
12.
J Crohns Colitis ; 13(4): 495-509, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30395194

RESUMO

BACKGROUND AND AIMS: The intestinal epithelium of inflammatory bowel disease [IBD] patients is exposed to various pro-inflammatory cytokines, most notably tumour necrosis factor alpha [TNF-α]. We have previously shown that the Notch signalling pathway is also upregulated in such an epithelium, contributing to intestinal epithelial cell [IEC] proliferation and regeneration. We aimed to reproduce such environment in vitro and explore the gene regulation involved. METHODS: Human IEC cell lines or patient-derived organoids were used to analyse Notch- and TNF-α-dependent gene expression. Immunohistochemistry was performed to analyse expression of ubiquitin D [UBD] in various patient-derived intestinal tissues. RESULTS: In human IEC cell lines, we found that Notch signalling and TNF-α-induced NFκB signalling are reciprocally regulated to promote expression of a specific gene subset. Global gene expression analysis identified UBD to be one of the most highly upregulated genes, due to synergy of Notch and TNF-α. The synergistic expression of UBD was regulated at the transcriptional level, whereas the UBD protein had an extremely short half-life due to post-translational, proteasomal degradation. In uninflamed intestinal tissues from IBD patients, UBD expression was limited to IECs residing at the crypt bottom. In contrast, UBD-expressing IECs were seen throughout the crypt in inflamed tissues, indicating substantial induction by the local inflammatory environment. Analysis using patient-derived organoids consistently confirmed conserved Notch- and TNF-α-dependent expression of UBD. Notably, post-infliximab [IFX] downregulation of UBD reflected favourable outcome in IBD patients. CONCLUSION: We propose that UBD is a novel inflammatory-phase protein expressed in IECs, with a highly rapid responsiveness to anti-TNF-α treatment.


Assuntos
Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Receptores Notch/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo , Antibacterianos/farmacologia , Linhagem Celular , Doxiciclina/farmacologia , Sinergismo Farmacológico , Células Epiteliais/metabolismo , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Infliximab/farmacologia , Infliximab/uso terapêutico , Mucosa Intestinal/metabolismo , NF-kappa B/metabolismo , Organoides/metabolismo , Receptores Notch/genética , Transdução de Sinais , Transcrição Genética , Transcriptoma , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
13.
Ir Med J ; 111(9): 820, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30556668

RESUMO

Aim Recent studies have suggested gender-specific differences with respect to both baseline disease activity and severity in ankylosing spondylitis (AS). Tumour necrosis factor inhibitors (TNFi) have shown significant benefit in AS but there may be gender-specific differences regarding responses to TNFi therapy. Methods AS patients with active disease despite adequate trials of NSAIDs were commenced on TNFi and followed in a biologic clinic between 2004 and 2011. Response to treatment was measured based on clinical and serological outcomes. Baseline radiographic data were also collected where available. Results 147 AS patients commenced TNFi therapy and were followed in a biologic clinic between 2004 and 2011. One-hundred and six (72%) of the patients were male and 90 (61%) were current or ex-smokers. The specific TNFi prescribed included etanercept (74 patients, 50.3%), adalimumab (51 patients, 34.7%), infliximab (21 patients, 14.2%) and golimumab (1 patient, 0.7%). The median mSASSS score was 11 (interquartile range 5-35). At baseline, the metrology indices (BASMI) were significantly lower in women (2.6 v 4; p=0.01) but all other clinical indices were similar. At 3 months, female patients had significantly worse median disease activity and functional indices (BASDAI: 4 v 2; p<0.01; BASFI: 3 v 2; p=0.03) than male patients. In addition, females had higher median ESR (19 v 6; p<0.01) which correlated with their disease activity indices (r=0.42, p=0.02). Discussion Despite similar disease activity at baseline, post-TNFi therapy women had significantly higher disease activity. Furthermore, ESR levels in women during therapy correlated with their clinical disease activity scores. Further exploration of these gender-specific differences is crucial for a greater understanding of the pathogenesis of AS as well as development of targeted therapies.


Assuntos
Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Etanercepte/uso terapêutico , Infliximab/uso terapêutico , Caracteres Sexuais , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacologia , Adulto , Anticorpos Monoclonais/farmacologia , Estudos de Coortes , Etanercepte/farmacologia , Feminino , Humanos , Infliximab/farmacologia , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/etiologia , Fatores de Tempo , Resultado do Tratamento
14.
Br J Hosp Med (Lond) ; 79(12): 686-693, 2018 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-30526103

RESUMO

The treatment of inflammatory bowel disease has changed dramatically over the last two decades. The arrival of infliximab as the first biological medicine for inflammatory bowel disease revolutionized its management. Since then the armamentarium of biological medicines for inflammatory bowel disease has grown to five drugs in three different classes. This article highlights the different mechanisms of action and describes the key evidence for their use including drug safety profiles. Furthermore it highlights the current National Institute for Health and Care Excellence recommendations for biological therapy in inflammatory bowel disease and discusses pending changes to the classic treatment algorithms in light of emerging evidence.


Assuntos
Produtos Biológicos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/fisiopatologia , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Infliximab/farmacologia , Infliximab/uso terapêutico , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/farmacologia , Ustekinumab/uso terapêutico
15.
Front Immunol ; 9: 2000, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30279689

RESUMO

Background: Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and chromosomal instability. Cutaneous granulomas are a known phenomenon in A-T but extra-dermal manifestation of granulomas at bone and synovia has not been reported so far. The clinical presentation, immunological findings, the long-term course and treatment options of eight patients with severe granulomas will be reported. Methods: From our cohort of 44 classical A-T patients, eight patients aged 2-11 years (18.2%) presented with granulomas. Immunological features of patients with and without granulomas were compared. Five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. Patients with significant extra-dermal involvement as well as one patient with massive skin manifestation were treated with TNF inhibitors. The patient with granulomas at his finger joint and elbow was treated with hematopoietic stem cell transplantation (HSCT). Results: Interestingly, seven of eight patients with granulomas were total IgA deficient, but there were no differences in IgG and IgM levels. All lymphocytes subsets were equally distributed except patients with granuloma had significantly lower naïve CD8 cells. In patients without treatment, four of eight showed a slow but significant enlargement of the granuloma. Treatment success with TNF inhibitors was variable. In one patient, treatment with TNF inhibitors led to a total remission for 3 years up to now. In two patients, treatment with TNF inhibitors led to a partial regression of granulomas. Treatment interruptions caused deterioration again. Conclusions: Granulomas in A-T progress slowly over years and can lead to significant morbidity.Treatment with TNF inhibitors was safe and in part successful in our patients. Interestingly HSCT leads to complete remission, and indicates that aberrant immune function is responsible for granulomas in A-T patients. What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients. AT A GLANCE COMMENTARY: Scientific knowledge on the subject: Little is known about the clinical presentation, course and treatment of granulomas in ataxia telangiectasia (A-T). In addition, this is the first report of extra-dermal manifestation of granulomas at bone and synovia in patients with A-T. What This Study Adds to the Field: Granulomas in A-T progress slowly over years and can lead to significant morbidity. Treatment with TNF inhibitors was safe and in part successful in our patients.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Ataxia Telangiectasia/terapia , Granuloma/terapia , Transplante de Células-Tronco Hematopoéticas , Infliximab/uso terapêutico , Dermatopatias/terapia , Adalimumab/farmacologia , Anti-Inflamatórios/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Infliximab/farmacologia , Masculino , Resultado do Tratamento
16.
J Immunother Cancer ; 6(1): 103, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305177

RESUMO

BACKGROUND: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. METHODS: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. RESULTS: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group. CONCLUSIONS: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.


Assuntos
Corticosteroides/uso terapêutico , Enterocolite/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Corticosteroides/farmacologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Infliximab/farmacologia , Masculino
17.
BioDrugs ; 32(6): 639-642, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30284704

RESUMO

PF-06438179/GP1111 (Zessly®; Ixifi®) [hereafter referred to as GP1111] is a biosimilar of the reference monoclonal anti-TNF-α antibody infliximab, and is approved in the EU and USA for the same indications as the reference drug, including rheumatoid arthritis (RA), Crohn's disease, ulcerative colitis (including paediatric ulcerative colitis in the EU), ankylosing spondylitis, psoriatic arthritis and plaque psoriasis; GP1111 is also approved in Japan. GP1111 has similar physicochemical characteristics and pharmacodynamic properties to those of reference infliximab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate-to-severe RA despite methotrexate therapy. GP1111 demonstrated clinical efficacy equivalent to that of reference infliximab in patients with moderate-to-severe RA, despite methotrexate therapy, and was generally well tolerated in this population. The tolerability, immunogenicity and safety profiles of GP1111 were similar to those of reference infliximab, and switching from reference infliximab to GP1111 had no impact on safety, efficacy or immunogenicity. The role of reference infliximab in the management of autoimmune inflammatory conditions is well established and GP1111 provides an effective biosimilar alternative for patients requiring infliximab therapy.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Substituição de Medicamentos , Infliximab/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Medicamentos Biossimilares/farmacologia , Humanos , Infliximab/farmacologia , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
18.
Mult Scler Relat Disord ; 26: 61-67, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30227311

RESUMO

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet. METHODS: In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy. RESULTS: We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy. CONCLUSION: A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated.


Assuntos
Anti-Inflamatórios/farmacologia , Autoanticorpos/sangue , Infliximab/farmacologia , Esclerose Múltipla/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/sangue , Neurite Óptica/sangue , Adolescente , Adulto , Estudos Transversais , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/tratamento farmacológico , Adulto Jovem
19.
Aliment Pharmacol Ther ; 48(9): 941-950, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30226271

RESUMO

BACKGROUND: Treatment paradigms for Crohn's disease with perianal fistulae (CD-pAF) are evolving. AIMS: To study the impact of multimodality treatment in CD-pAF on recurrence rates and the need for re-interventions and to identify predictive factors for these outcomes. METHODS: This was a multinational multicentre retrospective cohort study. Multimodality approach was defined as using a combination of medical treatments (anti-TNFs ± immunomodulators ± antibiotics) along with surgical approach (examination under anaesthesia (EUA) ± seton drainage) at diagnosis of CD-pAF. Univariable and multivariable analyses were performed for variables indicative of the need for reintervention. RESULTS: A total of 253 patients were included. 65% of patients received multimodality approach. Multimodality treatment resulted in complete fistula healing in 52% of patients. Re-intervention was needed in 27% of patients with simple and in 40.3% of those with complex fistula. On multivariable analysis multimodality treatment (OR: 0.35, 95% CI: 0.17-0.57, P = 0.001), seton removal (OR: 0.090, 95% CI: 0.027-0.30, P = 0.0001, therapy with infliximab (OR: 0.19, 95% CI: 0.06-0.64, P = 0.007), and therapy with adalimumab (OR: 0.12, "95% CI: 0.026-0.56, P = 0.007) were predictive of avoiding repeat surgery. Proctitis (OR: 3.76, 95% CI: 1.09-12.96, P = 0.03) was predictive of the need for radical surgery (proctectomy, diverting stoma) while multimodality treatment reduced the need for radical surgery (OR: 0.21, 95% CI: 0.05-0.81, P = 0.02). CONCLUSIONS: Multimodality treatment, anti-TNFs use, and removal of setons after multimodality treatment can result in improved outcomes in CD patients with perianal fistulae and reduce the need for repeat surgery and radical surgery.


Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Fármacos Gastrointestinais/uso terapêutico , Fístula Retal/tratamento farmacológico , Fístula Retal/cirurgia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Terapia Combinada/métodos , Doença de Crohn/epidemiologia , Drenagem/métodos , Feminino , Fármacos Gastrointestinais/farmacologia , Humanos , Infliximab/farmacologia , Infliximab/uso terapêutico , Internacionalidade , Masculino , Pessoa de Meia-Idade , Fístula Retal/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia , Adulto Jovem
20.
Immunotherapy ; 10(12): 1033-1039, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30185135

RESUMO

Administration of anti-TNFα agents has become a mainstay in the treatment of chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis. Adverse events, including infections and allergic reactions, have been reported. Malignancies are rare but potentially life threatening. The existence of bone tumor in those patients is very rare, only five cases of bone tumors were mentioned in juvenile idiopathic arthritis (JIA) in the literature. We describe three patients in whom bone neoplasms developed after years of anti-TNFα therapy for JIA or juvenile ankylosing spondylitis (JAS). One patient developed chondroblastoma, and the other two were diagnosed with osteosarcoma. Rheumatologists should increase their awareness of bone neoplasia in JIA or juvenile ankylosing spondylitis patients after anti-TNFα treatment.


Assuntos
Artrite Juvenil/tratamento farmacológico , Neoplasias Ósseas/diagnóstico , Condroblastoma/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Imunoterapia/métodos , Osteossarcoma/diagnóstico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/efeitos adversos , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Adolescente , Adulto , Artrite Juvenil/complicações , Neoplasias Ósseas/etiologia , Condroblastoma/etiologia , Etanercepte/efeitos adversos , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , Infliximab/efeitos adversos , Infliximab/farmacologia , Infliximab/uso terapêutico , Masculino , Osteossarcoma/etiologia , Adulto Jovem
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