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1.
Nihon Shokakibyo Gakkai Zasshi ; 118(1): 70-77, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33431752

RESUMO

A 22-year-old woman who was diagnosed with Crohn's disease experienced diarrhea and bloody stool. She was suspected of have aggravated Crohn's disease and was transferred to our hospital. Upper gastrointestinal endoscopy revealed multiple esophageal ulcers and erosive gastritis, while colonoscopy revealed multiple ulcers in the rectum to the sigmoid colon. Initially, the evidence suggested that the Crohn's disease had worsened, and consequently, prednisolone (PSL) therapy was initiated. However, the patient's condition was determined to be atypical inflammatory bowel disease, which was indicated by endoscopic findings and skin symptoms and because various test results did not meet the diagnostic criteria for Crohn's disease. As a result, her diagnosis was changed to granulomatosis with polyangiitis. Here, we report a case of granulomatosis with polyangiitis with gastrointestinal symptoms similar to Crohn's disease, both of which have been suggested to involve Th1/Th17 cells.


Assuntos
Doença de Crohn , Granulomatose com Poliangiite , Adulto , Colonoscopia , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Diarreia , Feminino , Hemorragia Gastrointestinal , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Adulto Jovem
2.
Postepy Biochem ; 66(3): 256-262, 2020 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-33315320

RESUMO

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases. The exact etiology of IBD is not well elucidated, however it is defined as a multifactorial disease. In addition, IBD carries the risk of serious complications and increases the risk of colorectal cancer. Also, in recent years, an increased rate of IBD cases has been noted. So far, there is no effective and well-defined therapy for IBD, and currently available drugs mainly provide symptomatic treatment. Unfortunately, conventional treatment does not always bring the expected benefits, moreover, it is often associated with unpleasant side effects. Currently, some research have been focused on unconventional forms of IBD treatment, testing therapies based on natural products. Individual polyphenols, as well as polyphenol-rich preparations and extracts are also valuable in IBD treatment through antioxidant, anti-inflammatory and bactericidal activity. Moreover, described here results of clinical trials suggest that polyphenols can alleviate symptoms and prevent recurrence of IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Polifenóis/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/microbiologia , Humanos , Doenças Inflamatórias Intestinais/microbiologia
3.
Acta Gastroenterol Belg ; 83(4): 657-659, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33321025

RESUMO

Discontinuation of treatment in children with inflammatory bowel disease (IBD) in long-term remission remains debatable. The risk of relapse is one of the main concerns in the consideration of reduction or cessation of treatment. In 2017 all paediatric IBD patients treated with originator infliximab at the Department of Paediatric Gastroenterology, Ghent University Hospital, were switched to biosimilar Remsima®. Faecal calprotectin, infliximab through levels and antibodies, white cell count, haemoglobin and C-reactive protein were measured before and after switching to biosimilar. In total 21 IBD patients (3 Ulcerative Colitis - 19 CD) between 7 and 15 years old were switched. Three (14%) patients with CD in clinical, biochemical and histological remission had an unmeasurable through level and antibodies for infliximab, after 22 to 82 months of use. Switching to another treatment or cessation was discussed with patients and parents, all 3 patients decided to stop treatment. All 3 are still in clinical remission 21 to 24 months after treatment stop. Six-monthly follow-up is foreseen.


Assuntos
Medicamentos Biossimilares , Doença de Crohn , Doenças Inflamatórias Intestinais , Adolescente , Medicamentos Biossimilares/uso terapêutico , Criança , Doença de Crohn/tratamento farmacológico , Substituição de Medicamentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Suspensão de Tratamento
4.
Artigo em Inglês | MEDLINE | ID: mdl-33331521

RESUMO

COVID-19 is a viral disease caused by SARS-CoV-2 that compromises the host immune response in severe cases, promoting a hyperinflammation that results in acute lung injury and multiple organs failure. In this context, patients presenting with immune-related diseases, such as Crohn's disease, affected by COVID-19, may have an uncertain prognosis. We report on a case of a young female patient with a severe Crohn's disease that presented with COVID-19 pneumonia and a favorable outcome even maintaining the use of adalimumab, TNF - alpha inhibitor and prednisone. This case raises the hypothesis that aside from prednisone, TNF-α inhibitors such as adalimumab could be used to stop the progression to COVID-19 complications by blocking the TNF-alpha-driven inflammatory process that occurs in severe COVID-19.


Assuntos
Adalimumab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Prednisona/uso terapêutico , Doença de Crohn/virologia , Feminino , Humanos , Inibidores do Fator de Necrose Tumoral/uso terapêutico
6.
Rev Assoc Med Bras (1992) ; 66(11): 1566-1572, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33295411

RESUMO

AIM: To compare the level of physical activity (PA), exercise capacity, and body composition before and after infliximab-induced clinical remission in patients with Crohn's disease (CD). METHODS: This prospective longitudinal study evaluated 44 adult outpatients with active CD before infliximab administration and 24 weeks after infliximab therapy. The patients were evaluated for PA in daily life, exercise capacity, muscle strength, and body composition. RESULTS: 38 (86.4%) patients achieved infliximab-induced remission at 24 weeks and presented an increment in the number of steps taken of 1092 (7440±2980 vs. 6348±3177, respectively; p=0.006). The inactive time was reduced when compared to the baseline value (454.2±106.3 vs. 427.9±97.8, respectively; p=0.033). There was no difference in the distance walked before and after infliximab therapy, while there was an increase in the fat mass index in responders to infliximab compared to the baseline (19.1±7.6 vs. 14.9±5.8; p=0.001). CONCLUSIONS: Infliximab-induced remission was shown to be effective for increasing physical activity by improving the number of steps and reducing inactive time. The maintenance of clinical remission associated with incentives to regular PA may contribute to making these patients reach an ideal level of PA.


Assuntos
Doença de Crohn , Doença de Crohn/tratamento farmacológico , Exercício Físico , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Estudos Longitudinais , Estudos Prospectivos
7.
Postepy Biochem ; 66(1): 42-48, 2020 03 31.
Artigo em Polonês | MEDLINE | ID: mdl-33320478

RESUMO

Sphingosine-1-phosphate (S1P) belongs to the group of biologically active sphingolipids. Because of its ability to regulate the migration of lymphocytes, S1P constitutes an important element of pathophysiology of several diseases, such as: lupus erythematosus, multiple sclerosis or inflammatory bowel diseases. Inflammatory bowel diseases (IBD) are the group of chronic and recurrent diseases of the gastrointestinal tract. The most common among IBD are: Crohn's disease and ulcerative colitis. Drugs that are currently used in the therapy of IBD alleviate symptoms, improve patients' quality of life and induce remission but their efficacy is not satisfactory. Modulators of S1P receptors constitu­te an emerging option in the therapy of IBD. In this review we will discuss the role of S1P, its receptor and enzymes that participate in the metabolism of S1P under physiological conditions and in the course of IBD. Moreover, we will sum up the results of preclinical and clinical studies on S1P receptors modulators in IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Humanos , Qualidade de Vida , Esfingosina/metabolismo
9.
Arq Bras Cir Dig ; 33(2): e1522, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33237166

RESUMO

BACKGROUND: Anti-TNF drugs are a fundamental part of the treatment of Crohn's disease (CD), so identifying factors related to loss of response is of great importance in clinical practice. AIM: Identify potential factors related to loss of response to anti-TNF agents in Crohn's disease patients. METHODS: This is a prospective study of CD patients attending a specialized outpatient clinic using a specific form, including patients with more than one year of follow-up on anti-TNF (Infliximab, Adalimumab or Certolizumab pegol). The information obtained was tabulated and analyzed to identify possible reasons for the loss of response to anti-TNF agents; results were submitted to statistical analysis by chi-square teste considering significant p<0.05. RESULTS: Sixty-four patients were included, most of them females (56.3%), predominant age group between 26 and 55 years, of whom 25 required optimization, 23 remained in remission with the usual dose and interval, and 16 required switch; most of those who needed switch had hematological problems such as anemia and/or had already undergone surgical treatment for CD. CONCLUSIONS: Anemia and prior CD surgery have been linked to loss of anti-TNF response.


Assuntos
Doença de Crohn/tratamento farmacológico , Tolerância a Medicamentos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Adulto , Doença de Crohn/cirurgia , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa , Adulto Jovem
10.
Am J Gastroenterol ; 115(11): 1768-1774, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33156094

RESUMO

INTRODUCTION: De-escalation of biologic therapy is a commonly encountered clinical scenario. Although biologic discontinuation has been associated with high rates of relapse, the effectiveness of dose de-escalation is unclear. This review was performed to determine the effectiveness of dose de-escalation of biologic therapy in inflammatory bowel disease. METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception to October 2019. Randomized controlled trials and observational studies involving dose de-escalation of biologic therapy in adults with inflammatory bowel disease in remission were included. Studies involving biologic discontinuation only and those lacking outcomes after dose de-escalation were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: We identified 1,537 unique citations with 20 eligible studies after full-text review. A total of 995 patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial. Seven studies included patients with Crohn's disease, 1 included patients with ulcerative colitis, and 12 included both. Overall, clinical relapse occurred in 0%-54% of patients who dose de-escalated biologic therapy (17 studies). The 1-year rate of clinical relapse ranged from 7% to 50% (6 studies). Eighteen studies were considered at high risk of bias, mostly because of the lack of a control group. DISCUSSION: Dose de-escalation seems to be associated with high rates of clinical relapse; however, the quality of the evidence was very low. Additional controlled prospective studies are needed to clarify the effectiveness of biologic de-escalation and identify predictors of success.


Assuntos
Produtos Biológicos/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Adalimumab/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Infliximab/administração & dosagem , Recidiva
11.
Am J Gastroenterol ; 115(11): 1812-1820, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33156100

RESUMO

INTRODUCTION: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort. METHODS: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method. RESULTS: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively. DISCUSSION: Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças do Ânus/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fístula Retal/tratamento farmacológico , Ustekinumab/uso terapêutico , Abscesso , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças do Ânus/fisiopatologia , Estudos de Coortes , Doença de Crohn/fisiopatologia , Intervalo Livre de Doença , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fístula Retal/fisiopatologia , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto Jovem
12.
Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med ; 28(Special Issue): 1137-1145, 2020 Oct.
Artigo em Russo | MEDLINE | ID: mdl-33219771

RESUMO

AIM: to estimate the quality and availability of medical care for patients with ulcerative colitis (UC) and Crohn's disease (CD), to assess the impact of the economic burden of these diseases on the healthcare budget of Russia and to systematize the main problems in the organization of medical care and drug supply for patients with inflammatory bowel diseases (IBD). Regional IBD databases (2016-2018), official statistical databases, costs of treatment and results of expert interviews with specialists in IBD were used in the study. The analyzed databases showed 104,668 patients with UC in Russia in 2018 (prevalence rate 71 per 100,000 people) and 66,647 patients with CD (prevalence rate of 45 per 100,000 people). The economic burden including agents for biologic therapy (ABT) for the UC was 39.54 billion rubles a year (495 rubles per capita), and CD - 32.98 billion rubles a year (378 rubles per capita). It requires an additional 9.87 billion rubles annually for UC and 9.20 billion rubles annually for CD patients to provide the complete supply with ABT. The annual burden of IBD is 72.52 billion rubles, which is comparable to the costs of other socially significant diseases, including malignant tumors. It shows the high social and economic value of IBD for the country. The main problems of medical care and drug supply for IBD patients are the mismatch of official statistical data and real IBD prevalence in Russia due to absence of comprehensive register and the insufficient supply with ABT due to limited funding. A federal center for IBD should be founded for better quality of registration, for the precise monitoring and for the active management of personal drug supply.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Efeitos Psicossociais da Doença , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Humanos , Federação Russa/epidemiologia
13.
Zhonghua Yi Xue Za Zhi ; 100(42): 3303-3308, 2020 Nov 17.
Artigo em Chinês | MEDLINE | ID: mdl-33202491

RESUMO

Objective: To explore the associations of regulatory B cells (Breg cells) and regulatory T cells (Treg cells) with the clinical effect of Infliximab in the treatment of Chinese patients with Crohn's disease (CD). Methods: From January 2017 to June 2019, a total of 32 CD patients at active stage and 33 age and gender-matched healthy controls were collected from the Second Affiliated Hospital of Wenzhou Medical University in this study. Approximate 5 ml of peripheral fasting venous blood was obtained from every subject. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood. Then multi-color flow cytometry was applied to determine the proportion of Breg (CD3-CD19+IL-10+B cells) in B cells and the proportion of Treg (CD4+CD25+Foxp3+T cells) in CD4+T cells. Infliximab (5 mg/kg) was given intravenously at week 0, 2 and 6 to induce CD remission, and then maintained with the same dose of Infliximab every 8 weeks. And the proportions of Breg and Treg were examined at week 14 of Infliximab treatment, then compared with those of week 0. Simultaneously, C-reactive protein (CRP), leucocyte count, platelet count, erythrocyte sedimentation rate were detected in CD patients to assess the clinical effect at week 0 and 14 of Infliximab treatment. Results: Before infliximab treatment, compared with healthy controls, the proportion of Breg in B cells was significantly increased [(3.15±1.17)% vs (2.64±0.38)%, P=0.024)], and the proportion of Treg in CD4+T cells was significantly decreased [(2.15±0.49)% vs (4.25±0.41)%, P<0.001] in CD patients. And the proportion of Breg was positively related with the proportion of Treg in CD patients either at week 0 or week 14 of Infliximab treatment (r=0.628, P<0.001; r=0.749, P<0.001). At week 14 of Infliximab treatment, according to symptoms, Crohn's disease activity index (CDAI) and endoscopic mucosal healing, CD patients were classified as remission group (CDAI<150 and endoscopic mucosal healing, R group) and non-remission group (CDAI≥150 or mucosal non-healing group, N group). Compared with CD patients at week 0 of Infliximab treatment, both the proportion of Breg and Treg were significantly enhanced [(5.89±2.60)% vs (3.19±1.27)%, P<0.001; (4.59±0.72)% vs (2.08±0.47)%, P<0.001], whereas CDAI and CRP was significantly reduced [CDAI: (63.19±14.69) vs (195.62±58.13), P<0.001; CRP: (3.65±2.23) mg/L vs (29.80±30.06) mg/L, P<0.001] in R group at week 14 of Infliximab treatment. The proportions of Breg and Treg were negatively related with the CRP (r=-0.279, P=0.026; r=-0.406, P=0.001) and CDAI (r=-0.409, P=0.001; r=-0.708, P<0.001) in CD patients at week 0 and 14 of Infliximab treatment. At week 14 of Infliximab treatment, ROC curve analysis showed that the predictive value of "Breg+Treg" for the effect of Infliximab was higher than the other parameters (area under ROC: 0.782, cutoff value: 0.895 5, P=0.034). Conclusions: Breg cells and Treg cells are not only significantly correlated with CD disease activity, but the combined detection of the two types of immune cells has higher clinical value for predicting the effect of Infliximab in CD patients at active stage.


Assuntos
Linfócitos B Reguladores , Doença de Crohn , Proteína C-Reativa , Doença de Crohn/tratamento farmacológico , Humanos , Infliximab/uso terapêutico , Linfócitos T Reguladores
14.
Pol Merkur Lekarski ; 48(287): 349-353, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33130798

RESUMO

Crohn's disease (CD) is a chronic and granulomatous inflammatory disease of the entire gastrointestinal tract. The etiopathogenesis is not fully elucidated. The most common symptoms in the active phase of the disease include abdominal pain, prolonged diarrhea, fever, fatigue, malaise and weight loss. Oral manifestations of CD are classified into specific for CD with granulomatous changes and non-specific ones. This rare extraintestinal manifestation of CD in adults may precede gastrointestinal tract involvement, occur together or appear after years of its duration. Oral lesions can be initiated by malnourishment, poor absorption of nutrients or side-effect of medications. A CASE REPORT: We describe a 28-year-old female with a 9-years CD history, who presented in the active disease with oral lesions. They were classified as non-specific ones, and included oral candidiasis, irregular erythematous patches on the cheek mucosa, exfoliative lip inflammation, and angular cheilitis. The patient was treated with azathioprine, and since the last exacerbation of symptoms, induction therapy with adalimumab, (anti-TNF-alpha), has been prescribed. Nystatin was applied to treat the oral lesions, based on the microbiological assessment of the Candida albicans susceptibility, and symptomatic treatment. After a two-week treatment the oral mucosa was healed and angular cheilitis showed marked improvement compared to the initial presentation. CONCLUSIONS: The young female with active CD presented the nonspecific lesions in the oral cavity. The lesions coexisted with the active inflammatory process in the intestinal tract with characteristic clinical symptoms, and were associated with sideropenic anemia. The implementation of the local therapy, systemic CD treatment and supplementation of micronutrient deficiencies have led to a healing of the oral lesions. We emphasize a personalized approach to treatment and close cooperation between the dentist and the gastroenterologist.


Assuntos
Doença de Crohn , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Adalimumab , Adulto , Azatioprina , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Fator de Necrose Tumoral alfa
15.
PLoS Med ; 17(10): e1003348, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33125391

RESUMO

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Produtos Biológicos/imunologia , Adalimumab/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Cadeias alfa de HLA-DQ/genética , Humanos , Imunossupressores/uso terapêutico , Infliximab/uso terapêutico , Interferon beta-1a/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Estudos Prospectivos , Rituximab/uso terapêutico
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