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3.
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
4.
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
6.
PLoS One ; 14(4): e0214857, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947317

RESUMO

Myasthenia gravis (MG) is an autoimmune disease. In recent years, considerable evidence has indicated that Gene Ontology (GO) functions, especially GO-biological processes, have important effects on the mechanisms and treatments of different diseases. However, the roles of GO functions in the pathogenesis and treatment of MG have not been well studied. This study aimed to uncover the potential important roles of risk-related GO functions and to screen significant candidate drugs related to GO functions for MG. Based on MG risk genes, 238 risk GO functions and 42 drugs were identified. Through constructing a GO function network, we discovered that positive regulation of NF-kappaB transcription factor activity (GO:0051092) may be one of the most important GO functions in the mechanism of MG. Furthermore, we built a drug-GO function network to help evaluate the latent relationship between drugs and GO functions. According to the drug-GO function network, 5 candidate drugs showing promise for treating MG were identified. Indeed, 2 out of 5 candidate drugs have been investigated to treat MG. Through functional enrichment analysis, we found that the mechanisms between 5 candidate drugs and associated GO functions may involve two vital pathways, specifically hsa05332 (graft-versus-host disease) and hsa04940 (type I diabetes mellitus). More interestingly, most of the processes in these two pathways were consistent. Our study will not only reveal a new perspective on the mechanisms and novel treatment strategies of MG, but also will provide strong support for research on GO functions.


Assuntos
Ontologia Genética , Redes Reguladoras de Genes , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/genética , Adalimumab/farmacologia , Carnosina/análogos & derivados , Carnosina/farmacologia , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Reposicionamento de Medicamentos , Etanercepte/farmacologia , Estudos de Associação Genética , Glucosamina/farmacologia , Humanos , Imunossupressores/farmacologia , Miastenia Gravis/imunologia , Compostos Organometálicos/farmacologia , Testes Farmacogenômicos , Talidomida/análogos & derivados , Talidomida/farmacologia , Compostos de Zinco/farmacologia
8.
Biologicals ; 58: 7-15, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30744947

RESUMO

A biosimilar is a biological medicinal product that is highly similar to an authorized biological product in terms of quality, biological activity, safety and efficacy. SB5 was developed by Samsung Bioepis as a biosimilar referencing adalimumab, and was authorized by the European Commission (EC) in August 2017 (Imraldi®). Extensive characterization studies were performed to demonstrate functional similarity of SB5 to reference adalimumab (Humira®, AbbVie Inc. and AbbVie Deutschland GmbH & Co. KG). SB5 and Humira® showed highly similar soluble TNF-α binding and neutralizing activity, as well as transmembrane TNF-α binding activity and reverse signaling induced in the membrane TNF-α expressing cell line. Both products exhibited similar binding of the Fc gamma receptors and Fc-related effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In addition, additional mechanisms of action induced by TNF-α, such as cytokine release and expression of adhesion molecules, were analyzed and shown to be similar between SB5 and Humira®. Taken together, our results demonstrate that SB5 and Humira® are highly similar in terms of their functional characteristics.


Assuntos
Adalimumab , Medicamentos Biossimilares , Adalimumab/farmacocinética , Adalimumab/farmacologia , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/normas , Humanos , Células Jurkat , Equivalência Terapêutica
9.
BioDrugs ; 33(1): 113-116, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30712241

RESUMO

FKB327 (Hulio®) is a biosimilar of the reference monoclonal anti-TNFα antibody adalimumab, and is approved in the EU for use in the same indications as reference adalimumab. FKB327 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and pharmacokinetic equivalence was shown in healthy volunteers and patients with moderate-to-severe rheumatoid arthritis (RA) despite methotrexate therapy. FKB327 demonstrated equivalent clinical efficacy to that of reference adalimumab in patients with moderate-to-severe RA, and similar tolerability, safety and immunogenicity profiles. Switching from reference adalimumab to FKB327 had no impact on efficacy, safety or immunogenicity.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Adalimumab/farmacologia , Medicamentos Biossimilares/farmacologia , Humanos , Metotrexato/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator de Necrose Tumoral alfa/metabolismo
10.
Dermatol Ther ; 32(2): e12793, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30515970

RESUMO

Psoriasis is a chronic, systemic inflammatory disease that in the moderate to severe forms may benefit of biologics, namely TNF and IL-12/23 and IL-17 inhibitors. Loss of response, lack of response, or discontinuation due to adverse events represent a concrete therapeutic challenge for dermatologists that have to switch patients to other treatments. Although some evidences already exist toward the switch from IL-12/23 and TNF inhibitors to IL-17 inhibitors, conversely nothing is present toward the switch from IL-17 inhibitors to IL-12/23 and TNF inhibitors. We performed a real-life study enrolling 50 patients randomly switched to adalimuamb, a TNF inhibitor, or ustekinumab, an IL-12/23 inhibitor. Our observational study suggests that switching from IL-17i to TNFi and IL-12/23i is a safe and effective therapeutic strategy.


Assuntos
Adalimumab/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Ustekinumab/administração & dosagem , Adalimumab/farmacologia , Adulto , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Estudos de Coortes , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Ustekinumab/farmacologia
11.
Dig Dis ; 37(2): 123-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30304717

RESUMO

BACKGROUND: This is the first retrospective report of pregnancy outcomes after exposure to adalimumab treatment in Japan. METHODS: Using the AbbVie safety database, we analyzed pregnancy outcome data from patients who received adalimumab treatment from April 16, 2008, to May 15, 2017. RESULTS: Data were extracted retrospectively for 74 pregnancies in 73 patients. More than half of the patients included in the study received adalimumab for the treatment of Crohn's disease (37.8%) or ulcerative colitis (20.3%), while 9.5% received adalimumab for rheumatoid arthritis. Of the 53 pregnancies with available outcome data, 45 newborns (45/53 [84.9%]) were delivered. Of these births, 30 were full-term, 2 were preterm, and 13 were unknown. Apgar scores were available for 11 of the 16 newborns whose mothers were exposed to adalimumab in the third trimester; all scores were within the normal range. Low birth weight was observed in 5 infants out of the 30 full-term deliveries. There were also 5 miscarriages (5/53 [9.4%]), 2 induced abortions (2/53 [3.8%]), and 1 stillbirth (1/53 [1.9%]). Eight maternal adverse events were observed in 5 pregnancies; no serious adverse events occurred. CONCLUSION: Although safety concerns were inconclusive, these data do not report additional risk to pregnancy outcomes with adalimumab exposure.


Assuntos
Adalimumab/uso terapêutico , Resultado da Gravidez , Adalimumab/efeitos adversos , Adalimumab/farmacologia , Adolescente , Adulto , Criança , Feminino , Feto/patologia , Humanos , Recém-Nascido , Japão , Nascimento Vivo , Pessoa de Meia-Idade , Gravidez , Terceiro Trimestre da Gravidez/efeitos dos fármacos , Estudos Retrospectivos , Adulto Jovem
12.
J Immunol Methods ; 464: 87-94, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30395815

RESUMO

The development of biotherapeutics requires continuous improvement in analytical methodologies for the assessment of their quality attributes. A subset of biotherapeutics is designed to interact with specific antigens that are exposed on the membranes of target cells or circulating in a soluble form, and effector functions are achieved via recognition of their Fc region by effector cells that induce mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). Thus, ADCC induction is a critical quality attribute (CQA) that must be evaluated to ensure biotherapeutic efficacy. Induction of ADCC can be evaluated by employing effector cells from different sources, such as peripheral blood mononuclear cells (PBMC) and genetically modified cell lines (e.g., transfected NKs or Jurkat cells), and different approaches can be used for detection and results interpretation depending on the type of effector cells used. In this regard, validation of the assays is relevant to ensure the reliability of the results according to the intended purpose. Herein, we show the standardization and validation of ADCC assays to test the potency of three biotherapeutic proteins using primary NK cells obtained from fresh blood as effector cells and detecting cell death by flow cytometry. The advantage of using primary NKs instead of modified cells is that the response is closer to that occurring in vivo since cytotoxicity is evaluated in a direct manner. Our results indicate that in all cases, the assays exhibited a characteristic sigmoidal dose/response curve complying with accurate, precise and specific parameters. Thereby, the validated ADCC assay is an appropriate alternative to evaluate the biological activities of these type of biotherapeutics.


Assuntos
Adalimumab/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Separação Celular/métodos , Etanercepte/farmacologia , Citometria de Fluxo , Células Matadoras Naturais/efeitos dos fármacos , Rituximab/farmacologia , Animais , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/patologia , Células CHO , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Células Matadoras Naturais/imunologia , Cultura Primária de Células , Reprodutibilidade dos Testes
13.
J Obstet Gynaecol Res ; 45(2): 358-367, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30358007

RESUMO

AIM: Ovarian torsion is a rare but an important reason of acute lower abdominal pain in women and associated with serious morbidity and mortality, if not treated promptly. The aim of this study was to evaluate the effects of an antitumor necrosis factor-α antibody on ovarian torsion in a rat model of ischemia-reperfusion (I/R) injury. METHODS: Forty female Wistar Albino rats were used in the present study. The rats were randomly divided into four groups: group I (sham), group II (I/R), group III (I/R + isotonic saline) and group IV (I/R + adalimumab). The I/R model was induced by torsion of both ovaries. Immunohistochemical staining for interleukin-1ß (IL-1ß), nuclear factor-κB (NF-κB), and inducible nitric oxide synthase was performed. Tissue and serum oxidative stress markers in conjunction with apoptotic index (AI) with the terminal deoxynucleotidyl transferase dUTP nick end labeling method were also calculated. RESULTS: Tissue total oxidant status, oxidative stress index and nitric oxide values were significantly decreased, and tissue total antioxidant status was found to be increased in group IV. Inflammation, vascular congestion and hemorrhagia were significantly lower in adalimumab-treated group. Serum oxidative stress markers and tissue malondialdehyde levels did not differ in study groups. The AI was significantly increased in groups 2 and 3. Adalimumab treatment significantly decreased the AI. CONCLUSION: Adalimumab therapy in rats attenuated I/R induced ovarian injury, possibly suppressing inflammation, inhibiting oxidative stress, and altering apoptotic pathways.


Assuntos
Adalimumab/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Doenças Ovarianas/tratamento farmacológico , Ovário/lesões , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Adalimumab/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Feminino , Distribuição Aleatória , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/imunologia
14.
Rheumatology (Oxford) ; 58(2): 352-360, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30376130

RESUMO

Objectives: ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA. Methods: Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach. Results: A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA. Conclusion: The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition. Trial registration: ClinicalTrials.gov, NCT02433340, NCT02349451.


Assuntos
Antirreumáticos/farmacologia , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulinas/farmacologia , Interleucina-17/antagonistas & inibidores , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Psoriásica/sangue , Artrite Reumatoide/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Imunoglobulinas/administração & dosagem , Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/antagonistas & inibidores
15.
Am J Clin Dermatol ; 20(1): 155-164, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30417277

RESUMO

BACKGROUND: Health-related quality of life (HRQoL) may be markedly impaired in patients with moderate-to-severe psoriasis. OBJECTIVES: Our objectives were to compare improvements in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) scores between patients receiving guselkumab compared with placebo or adalimumab and to correlate these improvements with skin clearance. METHODS: Pooled phase III VOYAGE 1 and VOYAGE 2 data were evaluated through week 24. At baseline, patients were randomized to guselkumab 100 mg, placebo, or adalimumab 40 mg. At week 16, patients receiving placebo switched to guselkumab. Assessment measures included DLQI percent change from baseline, DLQI 0/1, DLQI minimal clinically important difference (MCID), individual domain scores, PSSD symptoms and signs score = 0, DLQI association with PSSD, Investigator's Global Assessment (IGA), and Psoriasis Area and Severity Index (PASI). RESULTS: Significantly greater improvements from baseline DLQI were observed with guselkumab versus placebo (weeks 8 and 16) and versus adalimumab (week 24; p < 0.001). The proportion of patients achieving DLQI 0/1 ("no impact") at week 24 was higher with guselkumab than with adalimumab (58.9 vs. 40.2%; p < 0.001), and more patients attained a ≥ 4-point reduction in DLQI (MCID) at this timepoint (p < 0.001). Changes in individual DLQI domains were significantly greater for patients receiving guselkumab than for those receiving adalimumab, and among patients with individual baseline domain scores = 3 or 6 (severest impact), more guselkumab recipients than those receiving adalimumab achieved a score = 0 across all domains at week 24. DLQI 0/1 scores were associated with a PSSD symptom or sign score = 0 (no impact) and greater improvement of PASI and IGA (week 24). CONCLUSIONS: Pooled VOYAGE 1/VOYAGE 2 data demonstrated that guselkumab was superior to adalimumab in improving HRQoL, which was associated with greater skin clearance. CLINICAL TRIAL REGISTRATION: NCT02207231 and NCT02207244.


Assuntos
Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Psoríase/tratamento farmacológico , Adalimumab/farmacologia , Adulto , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Fármacos Dermatológicos/farmacologia , Esquema de Medicação , Feminino , Humanos , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/imunologia , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
16.
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
17.
Arthritis Res Ther ; 20(1): 268, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518408

RESUMO

BACKGROUND: Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. METHODS: In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. RESULTS: Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p < 0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p < 0.05; and 13.1, p < 0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-α inhibitors or interleukin-6 receptor inhibitor. CONCLUSIONS: Elevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression.


Assuntos
Artrite Reumatoide/terapia , Autofagossomos/metabolismo , Autofagia , Terapia Biológica/métodos , Inflamação/metabolismo , Adalimumab/farmacologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Autofagossomos/efeitos dos fármacos , Etanercepte/farmacologia , Feminino , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Metotrexato/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Proteína Sequestossoma-1/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
18.
BioDrugs ; 32(6): 635-638, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30460599

RESUMO

GP2017 (adalimumab) is a biosimilar anti-TNF-α antibody. It is approved in the EU for use in all indications for which reference adalimumab is approved. GP2017 has similar physicochemical and functional properties to those of reference adalimumab, and the pharmacokinetic similarity of the agent has been shown in healthy male volunteers. GP2017 demonstrated clinical efficacy equivalent to that of reference adalimumab in patients with moderate to severe plaque psoriasis or rheumatoid arthritis; the tolerability, safety and immunogenicity profiles of the two agents were also similar. Multiple switching between GP2017 and reference adalimumab (up to four times) had no impact on efficacy, tolerability or immunogenicity. The role of reference adalimumab in the management of autoimmune inflammatory conditions is well established and GP2017 provides an effective biosimilar alternative for patients requiring adalimumab therapy.


Assuntos
Adalimumab/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Substituição de Medicamentos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacologia , Doenças Autoimunes/imunologia , Medicamentos Biossimilares/farmacologia , Humanos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
19.
Cell Physiol Biochem ; 50(2): 525-537, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308514

RESUMO

BACKGROUND/AIMS: Psoriasis, an autoimmune diseases of the skin, characterized by patches of abnormal/inflammed skin, although not usually life-threatening, it causes severe discomfort, esthetic impairments, and may lead to impaired social functions and social withdrawal. Besides UV-phototherapy, various anti-inflammatory treatments are applied, depending on the severity of symptoms. In 2008, adalimumab (fully humanized human anti-TNF antibody) was launched for the treatment of psoriasis. In the quest to better understand the pathomechanism of adalimumab's therapeutic effects, and the acquired resistance to the drug, we have investigated how its administration affect the regulation of the expression of selected caspases, including those activated by inflammosome. METHODS: The research was initially carried out on normal human dermal fibroblasts (NHDF) treated with adalimumab for 2, 8 and 24 hours in vitro. Then, expression profile of genes encoding caspases and their regulatory micro-RNAs was determined with the use of oligonucleotide microarray. The validation of the microarray results was carried out by qRT-PCR. The in vitro study was followed by ex-vivo investigation of adalimumab's effects on the expression of caspase-6 in blood of the psoriatic patients. The samples were collected before, and 2 hours after adalimumab's administration and the analysis was determined by qRT-PCR. RESULTS: The result of the analysis indicated that introduction of adalimumab to the NHDF culture resulted in the change of the transcription activity of genes encoding caspases and genes encoding miRNAs. The analysis revealed 5 different miRNA molecules regulating the expression of: CASP2, CASP3 and CASP6. There were no statistically significant differences in the expression of gene encoding caspase-6 in the patients' blood before and 2 hours after the anti-TNF drug administration. CONCLUSION: We have found that adalimumab administration affects caspases expression, thus they may be used as molecular markers for monitoring the therapy with the use of an anti-TNF drugs, including adalimumab. It is likely that the mechanisms responsible for changed expression profiles of genes encoding caspase-2,-3, and -6, may be caused by the upregulation of the respective microRNA molecules. Increased expression of genes encoding specific caspases may induce inflammatory processes, as well as trigger apoptosis. Furthermore, the proapoptotic activity of caspases may be enhanced by miRNA molecules, which exhibit proapoptotic function. The overexpression of such miRNAs was observed in our study.


Assuntos
Adalimumab/farmacologia , Caspases/metabolismo , MicroRNAs/metabolismo , Psoríase/patologia , Transcriptoma/efeitos dos fármacos , Adalimumab/uso terapêutico , Caspases/genética , Linhagem Celular , Biologia Computacional , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Psoríase/tratamento farmacológico , Psoríase/genética , Fatores de Tempo
20.
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
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