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- Development and validation of risk matrices for Crohn's Disease outcomes in patients who underwent early therapeutic interventionsPublication . Dias, Cláudia Camila; Rodrigues, Pedro Pereira; Coelho, Rosa; Santos, Paula Moura; Fernandes, Samuel; Lago, Paula; Caetano, Cidalina; Rodrigues, Angela; Portela, Francisco; Oliveira, Ana; Ministro, Paula; Cancela, Eugenia; Vieira, Ana Isabel; Barosa, Rita; Cotter, Jose; Carvalho, Pedro; Cremers, Isabelle; Trabulo, Daniel; Caldeira, Paulo; Antunes, Artur; Rosa, Isadora; Moleiro, Joana; Peixe, Paula; Herculano, Rita; Gonçalves, Raquel; Gonçalves, Bruno; Sousa, Helena Tavares; Contente, Luis; Morna, Henrique; Lopes, Susana; Magro, FernandoIntroduction: The establishment of prognostic models for Crohn's disease [CD] is highly desirable, as they have the potential to guide physicians in the decision-making process concerning therapeutic choices, thus improving patients' health and quality of life. Our aim was to derive models for disabling CD and reoperation based solely on clinical/demographic data. Methods: A multicentric and retrospectively enrolled cohort of CD patients, subject to early surgery or immunosuppression, was analysed in order to build Bayesian network models and risk matrices. The final results were validated internally and with a multicentric and prospectively enrolled cohort. Results: The derivation cohort included a total of 489 CD patients [64% with disabling disease and 18% who needed reoperation], while the validation cohort included 129 CD patients with similar outcome proportions. The Bayesian models achieved an area under the curve of 78% for disabling disease and 86% for reoperation. Age at diagnosis, perianal disease, disease aggressiveness and early therapeutic decisions were found to be significant factors, and were used to construct user-friendly matrices depicting the probability of each outcome in patients with various combinations of these factors. The matrices exhibit good performance for the most important criteria: disabling disease positive post-test odds = 8.00 [2.72-23.44] and reoperation negative post-test odds = 0.02 [0.00-0.11]. Conclusions: Clinical and demographical risk factors for disabling CD and reoperation were determined and their impact was quantified by means of risk matrices, which are applicable as bedside clinical tools that can help physicians during therapeutic decisions in early disease management.
- Sexual quality of life in inflammatory bowel disease: A multicenter, national-level studyPublication . Roseira, Joana; Magro, Fernando; Fernandes, Samuel; Simoes, Carolina; Portela, Francisco; Vieira, Ana Isabel; Patita, Marta; Leal, Carina; Lago, Paula; Caldeira, Paulo; Gago, Tania; Currais, Pedro; Dias, Claudia Camila; Santiago, Mafalda; Dias, Sandra; Sousa, Helena TavaresBackground: The impact of inflammatory bowel disease (IBD) on sexual health is a leading concern among patients. Most studies focus on sexual dysfunction rather than patient-perceived sexual quality of life (SQoL). We aimed to assess SQoL in IBD patients compared with healthy controls. Methods: This is a multicenter, cross-sectional study of IBD patients (n = 575 with Crohn's disease and n = 294 with ulcerative colitis), compared with healthy controls (n = 398), that used an anonymous self-administered questionnaire. This multimodal questionnaire included sociodemographic data and 4 validated instruments: Short IBD Questionnaire, Social Desirability Scale, Sexual QoL Questionnaire-Male/Female, Nine-item Patient Health Questionnaire. Results: Inflammatory bowel disease patients reported lower SQoL (men: 77.29 vs 83.83; P < 0.001; women: 70.40 vs 81.63; P < 0.001) compared with controls. Among IBD patients, SQoL was positively correlated with health-related quality of life (HRQoL) and negatively correlated with depression symptoms. Perianal disease was associated with lower HRQoL and higher incidence of depression, but only impacted SQoL in men. In linear regression analysis for men, SQoL was associated with age, marital status, and depression (beta, -2.101; 95% confidence interval [CI], -2.505 to -1.696; P < 0.001). In women, SQoL was associated with depression (beta, -1.973; 95% CI, -2.313 to -1.632; P < 0.001) only. Conclusions: Patients with IBD had impaired SQoL compared with healthy controls. Age, widow status, and depression were independent predictors of SQoL in men with IBD, whereas in women depression was the only independent predictor. Emotional and self-esteem issues were the main concerns reported by IBD patients regarding sexual health.
- Proactive therapeutic drug monitoring of infliximab: a comparative study of a new point-of-care quantitative test with two established ELISA assaysPublication . Afonso, J.; Lopes, S.; Gonçalves, R.; Caldeira, Paulo; Lago, P.; Sousa, Helena Tavares; Ramos, J.; Gonçalves, A. R.; Ministro, P.; Rosa, I.; Vieira, A. I.; Dias, C. C.; Magro, F.BackgroundTherapeutic drug monitoring is a powerful strategy known to improve the clinical outcomes and to optimise the healthcare resources in the treatment of autoimmune diseases. Currently, most of the methods commercially available for the quantification of infliximab (IFX) are ELISA-based, with a turnaround time of approximately 8h, and delaying the target dosage adjustment to the following infusion.AimTo validate the first point-of-care IFX quantification device available in the market - the Quantum Blue Infliximab assay (Buhlmann, Schonenbuch, Switzerland) - by comparing it with two well-established methods.MethodsThe three methods were used to assay the IFX concentration of spiked samples and of the serum of 299 inflammatory bowel diseases (IBD) patients undergoing IFX therapy.ResultsThe point-of-care assay had an average IFX recovery of 92%, being the most precise among the tested methods. The Intraclass Correlation Coefficients of the point-of-care IFX assay vs. the two ELISA-based established methods were 0.889 and 0.939. Moreover, the accuracy of the point-of-care IFX compared with each of the two reference methods was 77% and 83%, and the kappa statistics revealed a substantial agreement (0.648 and 0.738).ConclusionsThe Quantum Blue IFX assay can successfully replace the commonly used ELISA-based IFX quantification kits. This point-of-care IFX assay is able to deliver the results within 15min makes it ideal for an immediate target concentration adjusted dosing. Moreover, it is a user-friendly desktop device that does not require specific laboratory facilities or highly specialised personnel.
- Evaluation of MGP gene expression in colorectal cancerPublication . Caiado, Helena; Conceição, Natércia; Tiago, Daniel; Marreiros, Ana; Vicente, Susana; Enriquez, Jose Luis; Vaz, Ana Margarida; Antunes, Artur; Guerreiro, Horacio; Caldeira, Paulo; Leonor Cancela, M.Purpose: Matrix Gla protein (MGP) is a vitamin K-dependent, gamma-carboxylated protein that was initially found to be a physiological inhibitor of ectopic calcifications affecting mainly cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for a human pathology, the Keutel syndrome, characterized by abnormal calcifications in cartilage, lungs, brain and vascular system. MGP was recently implicated in tumorigenic processes such as angiogenesis and shown to be abnormally regulated in several tumors, including cervical, ovarian, urogenital and breast. This fact has triggered our interest in analyzing the expression of MGP and of its regulator, the transcription factor runt related transcription factor 2 (RUNX2), in colorectal cancer (CRC). Methods: MGP and RUNX2 expression were analyzed in cancer and non-tumor biopsies samples from 33 CRC patients and 9 healthy controls by RT-qPCR. Consequently, statistical analyses were performed to evaluate the clinical-pathological significance of MGP and RUNX2 in CRC. MGP protein was also detected by immunohistochemical analysis. Results: Showed an overall overexpression of MGP in the tumor mucosa of patients at mRNA level when compared to adjacent normal mucosa and healthy control tissues. In addition, analysis of the expression of RUNX2 mRNA demonstrated an overexpression in CRC tissue samples and a positive correlation with MGP expression (Pearson correlation coefficient 0.636; p <= 0.01) in tumor mucosa. However correlations between MGP gene expression and clinical-pathological characteristics, such as gender, age and pathology classification did not provide relevant information that may shed light towards the differences of MGP expression observed between normal and malignant tissue. Conclusions: We were able to associate the high levels of MGP mRNA expression with a worse prognosis and survival rate lower than five years. These results contributed to improve our understanding of the molecular mechanism underlying MGP deregulation in cancer.
- Olmesartan-induced enteropathy: an unusual cause of villous atrophyPublication . Eusébio, Marta; Caldeira, Paulo; Antunes, Artur Gião; Ramos, André; Velasco, Francisco; Cadill, Jesús; Guerreiro, HoracioWe report a case of a 63-year-old-man presenting with chronic diarrhea and weight loss while on olmesartan treatment for hypertension. Investigation showed multiple nutritional deficiencies associated with diffuse intestinal villous atrophy. Serologies for celiac disease were negative and other causes of villous atrophy were excluded. Olmesartan as a precipitant agent was suspected and withdrawn. Clinical improvement occurred in days with no need for other therapeutic measures. Follow-up at three months showed clinical remission and almost complete recovery of intestinal atrophy. Olmesartan is an angiotensin receptor blocker commonly prescribed for the management of hypertension. Spruelike enteropathy associated with this drug is a recently described entity with few cases reported. It presents with chronic diarrhea and intestinal villous atrophy and should be included in its differential diagnosis. This case intends to alert clinicians for the possibility of this event in a patient on treatment with this drug.
- Risk factors for severity and recurrence of colonic diverticular bleedingPublication . Joaquim, Natércia; Caldeira, Paulo; Antunes, Artur; Eusébio, Marta; Guerreiro, HoracioBackground: Colonic diverticular bleeding is the most common cause of lower gastrointestinal bleeding. Risk factors related to severity and repeated bleeding episodes are not completely clearly defined. Objective: To characterize a Portuguese population hospitalized due to colonic diverticular bleeding and to identify the clinical predictors related to bleeding severity and rebleeding. Methods: Retrospective analysis of all hospitalized patients diagnosed with colonic diverticular bleeding from January 2008 to December 2013 at our institution. The main outcomes evaluated were bleeding severity, defined as any transfusion support requirements and/or signs of hemodynamic shock, and 1-year recurrence rate. Results: Seventy-four patients were included, with a mean age of 75.7 +/- 9.5 years; the majority were male (62.2%). Thirty-six patients (48.6%) met the criteria for severe bleeding; four independent risk factors for severe diverticular bleeding were identified: low hemoglobin level at admission (<= 11 g/dL; OR 18.8), older age (>= 75 years; OR 4.7), bilateral diverticular location (OR 14.2) and chronic kidney disease (OR 5.6). The 1-year recurrence rate was 12.9%. We did not identify any independent risk factor for bleeding recurrence in this population. Conclusion: In this series, nearly half of the patients hospitalized with diverticular bleeding presented with severe bleeding. Patients with low hemoglobin levels, older age, bilateral diverticular location and chronic kidney disease had a significantly increased risk for severe diverticular bleeding. In addition, a small number of patients rebled within the first year after the index episode, although we could not identify independent risk factors associated with the recurrence of diverticular bleeding.
- Clinical performance of an infliximab rapid quantification assayPublication . Magro, Fernando; Afonso, Joana; Lopes, Susana; Coelho, Rosa; Gonçalves, Raquel; Caldeira, Paulo; Lago, Paula; Sousa, Helena Tavares; Ramos, Jaime; Gonçalves, Ana Rita; Ministro, Paula; Rosa, Isadora; Meira, Tania; Andrade, Patrícia; Soares, João-Bruno; Carvalho, Diana; Sousa, Paula; Vieira, Ana Isabel; Lopes, Joanne; Dias, Cláudia Camila; Geboes, Karel; Carneiro, FátimaBackground: Therapeutic drug monitoring (TDM)-based algorithms can be used to guide infliximab (IFX) adjustments in inflammatory bowel disease (IBD) patients. This study aimed to explore a rapid IFX-quantification test from a clinical perspective. Methods: This manuscript describes a prospective cohort study involving 110 ulcerative colitis (UC) patients on the maintenance phase of IFX. IFX trough levels were quantified using a rapid quantification assay and a commonly-used reference kit. Results: Irrespective of the assay used to measure IFX, its through levels were statistically different between patients with and without endoscopic remission (Mayo endoscopic score = 0), as well as between patients stratified by their faecal calprotectin (FC) levels. Despite the fact that the two methods correlated well with each other [Spearman's rank correlation coefficient = 0.843, p < 0.001; intraclass correlation coefficients = 0.857, 95% confidence interval (CI): 0.791-0.903], there was a discernible systematic variation; values obtained with the reference kit were on average 2.62 units higher than those obtained with the rapid assay. Notwithstanding, 3 mu g/ml was shown to be an acceptable cut-off to assess endoscopic status and inflammatory burden levels using both assays. The percentage of patients that had a positive outcome when the IFX concentration measured by the rapid assay ranked above 3 mu g/ml was 88% both for a Mayo endoscopic score <= 1 and for an FC concentration <250 mu g/g. Conclusions: Based on this study, we concluded that using the rapid IFX assessment system with a 3 mu g/ml threshold is a reliable alternative to the time-consuming enzyme-linked immunosorbent assays in patients on the maintenance phase of IFX.
- Calprotectin and the Magnitude of Antibodies to Infliximab in Clinically-stable Ulcerative Colitis Patients are More Relevant Than Infliximab Trough Levels and Pharmacokinetics for Therapeutic EscalationPublication . Magro, Fernando; Afonso, Joana; Lopes, Susana; Coelho, Rosa; Gonçalves, Raquel; Caldeira, Paulo; Lago, Paula; Sousa, Helena Tavares; Ramos, Jaime; Gonçalves, Ana Rita; Ministro, Paula; Rosa, Isadora; Vieira, Ana Isabel; Andrade, Patrícia; Soares, João-Bruno; Carvalho, Diana; Sousa, Paula; Meira, Tania; Lopes, Joanne; Moleiro, Joana; Dias, Cláudia Camila; Falcão, Amilcar; Geboes, Karel; Carneiro, FátimaAlthough infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62 mu g/mL vs. 1.15 mu g/mL, p=0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI concentration below 3 mu g/mL (HR = 0.119, p = 0.010), and increased for patients with fecal calprotectin (FC) level above 250 mu g/g (HR = 9.309, p = 0.018). In clinically-stable UC patients, IFX pharmacokinetic features cannot predict therapeutic response on a short-term basis. However, high levels of ATIs or FC may be indicative of a future therapeutic escalation. (C) 2017 The Authors. Published by Elsevier B.V.
- Impact of early surgery and immunosuppression on Crohn's disease disabling outcomesPublication . Magro, Fernando; Dias, Cláudia C.; Coelho, Rosa; Santos, Paula M.; Fernandes, Samuel; Caetano, Cidalina; Rodrigues, Angela; Portela, Francisco; Oliveira, Ana; Ministro, Paula; Cancela, Eugenia; Vieira, Ana I.; Barosa, Rita; Cotter, Jose; Carvalho, Pedro; Cremers, Isabelle; Trabulo, Daniel; Caldeira, Paulo; Antunes, Artur; Rosa, Isadora; Moleiro, Joana; Peixe, Paula; Herculano, Rita; Gonçalves, Raquel; Gonçalves, Bruno; Sousa, Helena Tavares; Contente, Luis; Morna, Henrique; Lopes, SusanaBackground and Aims: The definition of early therapeutic strategies to control Crohn's disease aggressiveness and prevent recurrence is key to improve clinical practice. This study explores the impact of early surgery and immunosuppression onset in the occurrence of disabling outcomes. Methods: This was a multicentric and retrospective study with 754 patients with Crohn's disease, who were stratified according to the need for an early surgery (group S) or not (group I) and further divided according to the time elapsed from the beginning of the follow-up to the start of immunosuppression therapy. Results: The rate of disabling events was similar in both groups (S: 77% versus I: 76%, P = 0.700). The percentage of patients who needed surgery after or during immunosuppression therapy was higher among group S, both for first surgeries after the index event (38% of groups S versus 21% of group I, P, 0.001) and for reoperations (38% of groups S versus 12% of group I, P < 0.001). The time elapsed to reoperation was shorter in group I (HR = 2.340 [1.367-4.005]), stratified for the onset of immunosuppression. Moreover, reoperation was far more common among patients who had a late start of immunosuppression (S-36: 50% versus S0-6: 27% and S6-36: 25%, P < 0.001) and (I-36: 16% versus I0-6: 5% and I6-36: 7%, P, 0.001). Conclusions: Although neither early surgery nor immunosuppression seem to be able to prevent global disabling disease, an early start of immunosuppression by itself is associated with fewer surgeries and should be considered in daily practice as a preventive strategy.
- Ulcerative colitis: let's talk about extentPublication . Vaz, A.; Eusébio, Marta; Antunes, A.; Queiros, P.; Gago, T.; Belo, T.; Caldeira, Paulo; Guerreiro, H.Ulcerative colitis (UC) is a chronic inflammatory disease in which clinical course varies substantially between patients. The extent of the disease is usually pointed out as one of the factors responsible for this variation. With this study, we pretended to evaluate the differences in natural history and pharmacological therapy prescription between left-sided and extended UC.