The Mesoionic 1,3,4-thiadiazolium Derivative, MI-D, is a Potential Drug for Treating Glioblastoma by Impairing Mitochondrial Functions Linked to Energy Provision in Glioma Cells.

BACKGROUND: Mesoionic compound MI-D possesses important biological activities, such as antiinflammatory and antitumoral against melanoma and hepatocarcinoma. Glioblastoma is the most aggressive and common central nervous system tumor in adults. Currently, chemotherapies are not entirely effective, and the survival of patients diagnosed with glioblastoma is extremely short. OBJECTIVE: In this study, we aimed to evaluate the cytotoxicity of MI-D in noninvasive A172 glioblastoma cells and establish which changes in functions linked to energy provision are associated with this effect. METHODS: Cells A172 were cultured under glycolysis and phosphorylation oxidative conditions and evaluated: viability by the MTT method, oxygen consumption by high-resolution respirometry, levels of pyruvate, lactate, citrate, and ATP, and glutaminase and citrate synthase activities by spectrophotometric methods. RESULTS: Under glycolysis-dependent conditions, MI-D caused significant cytotoxic effects with impaired cell respiration, reducing the maximal capacity of the electron transport chain. However, A172 cells were more susceptible to MI-D effects under oxidative phosphorylation-dependent conditions. At the IC25, inhibition of basal and maximal respiration of A172 cells was observed, without stimulation of the glycolytic pathway or Krebs cycle, along with inhibition of the activity of glutaminase enzyme, resulting in a 30% ATP deficit. Additionally, independent of metabolic conditions, MI-D treatment induced cell death in A172 cells by apoptosis machinery/ processes. CONCLUSION: The impairment of mitochondrial respiration by MI-D under the condition sustained by oxidative phosphorylation may enhance the cytotoxic effect on A172 glioma cells, although the mechanism of cell death relies on apoptosis.

Factors Associated With Long Survival in Patients With Cancer Admitted to Palliative Care: An Exploratory Study.

Objective: Some patients with cancer admitted to palliative care have relatively long survivals of 1 year or more. The objective of this study was to find out factors associated with prolonged survival. Methods: Retrospective case-control study comparing the available data of patients with cancer who survived more than 1 year after admission in a palliative care service with patients with cancer who survived 6 months or less. The intended proportion was 4 controls for each case. Patients were identified through electronic records from 2012 until 2018. Results: And 1721 patients were identified. Of those patients, 111 (6.4%) survived for at least 1 year, and 363 (21.1%) were included as controls according to the established criteria. The intended proportion could not be reached; the proportion was only 3.3:1. The median survival of cases was 581 days (range: 371-2763), and the median survival of controls was 57 days (range: 1-182). In the multivariable analysis, patients with a hemoglobin ≥ 10.6 g/dL and a creatinine level >95 µmol/L had a higher probability of living more than 1 year. In contrast, patients with abnormal cognition, pain, anorexia, liver metastases, an Eastern Cooperative Oncology Group performance status >1, and a neutrophil/lymphocyte ratio ≥ 3.43 had a low probability of living more than 1 year. Conclusion: Several factors were statistically associated positively or negatively with prolonged survival. However, the data of this study should be confirmed in other studies.

PD-L1 expression in EBV associated gastric cancer: a systematic review and meta-analysis.

OBJECTIVES: The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC). MATERIALS AND METHODS: For this study, PubMed®, EMBASE® and Web of Science® databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis. RESULTS: The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p < 0.001), with a high heterogeneity between the included studies, which was associated with variation on positivity criteria for PD-L1 expression. Overall, the study reveals an increased association between PD-L1 and EBVaGC (OR = 6.36, 95% CI 3.91-10.3, p < 0.001). Furthermore, the study revealed that GC with lymphoid stroma (GCLS) is highly associated with EBV (OR = 17.4, 95% CI 6.83-44.1, p < 0.001), with a pooled EBV positivity rate of 52.9% (p < 0.001). CONCLUSIONS: Patients with EBVaGC tend to show higher PD-L1 expression, which enhances EBV positivity as a promising marker for patient selection for immunotherapy targeted agents. A uniform criteria for PD-L1 positivity in tumor cells is needed, as well as further prospective studies to validate our findings and their prognostic significance.

The Impact of COVID-19 Pandemic in Portuguese Cancer Patients: A Retrospective Study.

Literature reports that SARS-CoV-2 infection in cancer patients may be associated with higher severity and mortality, nevertheless the knowledge is limited. We aimed to describe patients' demographic characteristics and COVID-19 disease outcomes in Portuguese cancer patients. We conducted a retrospective study in a cohort of cancer patients diagnosed with COVID-19. A total of 127 individuals were included: 46.5% males and 53.5% females, with a median age of 72 years. Clinicopathological characteristics were used in univariate and multivariable logistic regression analyses to estimate odds ratios for each variable with outcomes adjusting for potential confounders. Our cohort revealed that 84.3% of patients had more than one risk factor for severe disease rather than cancer. In total, 36.2% of patients were admitted to the Department of Internal Medicine, 14.2% developed severe disease, 1.6% required Intensive Care Unit, and mortality was observed in 11.8%. Severe COVID-19 disease was associated with unfit (ECOG PS > 2) patients (p = 0.009; OR = 6.39; 95% CI: 1.60-25.59), chronic kidney disease (p = 0.004; OR = 20.7; 95% CI: 2.64-162.8), immunosuppression (p < 0.001; OR = 10.3; 95% CI: 2.58-41.2), and presence of respiratory symptoms at diagnosis (p = 0.033; OR = 5.05; 95% CI: 1.14-22.4). Increased risk for mortality was associated with unfit patients (p = 0.036; OR = 4.22; 95% CI: 1.10-16.3), cardiac disease (p = 0.003; OR = 8.26; 95% CI: 2.03-33.6) and immunosuppression (p = 0.022; OR = 5.06; 95% CI: 1.27-20.18). Our results demonstrated that unfit and immunosuppressed patients, with chronic kidney disease and cardiac disease, have, respectively, an increased risk for severe disease and mortality related to COVID-19. Hence, this study provides important information on risk factors for severe COVID-19 disease and associated mortality in a Portuguese cancer population.

Breast Cancer Metastasis in a Renal Carcinoma Pulmonary Metastasis: A Rare Example of Tumor-to-Tumor Metastasis.

The tumor-to-tumor metastasis phenomenon remains fairly uncommon, with fewer than 100 cases described to present time. Virtually any tumor can be a donor or a recipient neoplasm. Nevertheless, renal carcinomas have been implicated as the most common malignant tumors to harbor metastasis, while lung and breast tumors are the most frequent donors. This article reports an extremely rare case of a breast cancer metastasis in a lung metastasis of clear cell type renal cell carcinoma that met all Campbell and coworkers' tumor-to-tumor metastasis criteria. Additionally, we present the literature case reports of breast cancer metastasis in renal cell carcinomas and try to discuss the mechanisms underlying its occurrence. Since this phenomenon identification will impact the therapeutic strategy and it is not easily detected by image, the anatomopathological study of any and all suspicious lesions is of crucial importance. To the best of our knowledge, this is the first report of a metastasis inside a metastasis.

Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis.

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.

Evaluation of a clinical pharmacogenetics model to predict methotrexate response in patients with rheumatoid arthritis.

Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit. Here, we have revised the value of the CP-MTX model directly addressing its clinical benefit by focusing on the expected benefit-cost of the predictions. In addition, our study included a much larger number of RA patients (n = 720) in MTX monotherapy than previous studies. Benefit of CP-MTX prediction was defined as the patients that would have received combination therapy as first treatment because they were correctly predicted as non-responders to MTX monotherapy. In contrast, cost of CP-MTX prediction was defined as the responder patients that were wrongly predicted as non-responders. Application of CP-MTX predictions to our patients showed a good benefit-cost relationship, with half of the 66.7% non-responders to MTX monotherapy rightly directed to alternative treatments (a benefit of 33.3%) at the cost of 8.5% wrongly predicted non-responders. These benefits-costs were consistent with reanalysis of the previously published studies. Therefore, predictions of CP-MTX showed a good benefit-cost relationship for informing MTX prescription.

Liquid chromatographic methods for the therapeutic drug monitoring of methotrexate as clinical decision support for personalized medicine: A brief review.

Methotrexate (MTX) is an antifolate drug used for several diseases. Depending on the disease, MTX can be administered at low dose (LDMTX) in some autoimmune diseases, like rheumatoid arthritis, or at high dose (HDMTX) in some cancers, such as acute lymphoblastic leukemia. After absorption, MTX is metabolized in the liver to 7-hydroxymethotrexate and in the intestine to 2,4-diamino-N10-methylpteroic acid (DAMPA). Moreover, inside red blood cells, MTX is converted to active metabolites, MTX polyglutamates (MTXPGs), contributing to its pharmacodynamics. Owing to its narrow therapeutic range, and inter- and intra-patient variability, either noneffectiveness and/or toxicity may occur. Because of the existence of a relationship between drug therapeutic outcome and its systemic concentration, therapeutic drug monitoring (TDM) may ensure the effectiveness and safety of MTX use. In order to monitor the optimization of patient clinical response profile, several analytical methods have been described for TDM in biological samples. These include liquid chromatography (LC) coupled with ultraviolet detection, fluorescence detection or mass spectrometry, each one presenting advantages and drawbacks. This paper reviews the most commonly used techniques for sample preparation and critically discusses the current LC methods applied for the TDM of MTX in biological samples, at LDMTX and HDMTX.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review.

Bladder cancer is the most common malignancy of the urinary tract, presents the highest recurrence rate among solid tumors and is the second leading cause of death in genitourinary cancers. Despite recent advances in understanding of pathophysiology of the disease, the management of bladder cancer patients remains a clinically challenging problem. Particularly, bladder tumors invading the muscularis propria and disseminated disease are often not responsive to currently available therapeutic approaches, which include surgery and conventional chemotherapy. Antibody-based therapeutic strategies have become an established treatment option for over a decade in several types of cancer. However, bladder cancer has remained mostly an "orphan disease" regarding the introduction of these novel therapeutics, which has been translated in few improvements in patients overall survival. In order to shift this paradigm, several clinical studies involving antibody-based therapeutic strategies targeting the most prominent bladder cancer-related biomolecular pathways and immunological mediators are ongoing. This systematic review explores antibody-based therapeutics for bladder cancer undergoing clinical trial and discusses the future perspectives in this field, envisaging the development of more effective guided therapeutics.

SLC19A1, SLC46A1 and SLCO1B1 polymorphisms as predictors of methotrexate-related toxicity in Portuguese rheumatoid arthritis patients.

Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity.

Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms.

OBJECTIVE: Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. METHODS: Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. RESULTS: Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. CONCLUSION: Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.

Thymidylate synthase polymorphisms are associated to therapeutic outcome of advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.

Thymidylate synthase (TYMS) has three polymorphisms that may modulate thymidylate synthase (TS) expression levels: (1) 28 base pairs (bp) variable number tandem repeat (VNTR) (rs34743033); (2) single nucleotide polymorphism (SNP) C>G at the twelfth nucleotide of the second repeat of 3R allele (rs2853542); and (3) 6 bp sequence deletion (1494del6, rs34489327). This study was conducted to evaluate the influence of TYMS polymorphisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no statistically significant differences between VNTR genotypes; although, considering the SNP C>G, homozygotes 3RG presented a better prognostic at 36 months (p=0.004) and overall survival (p=0.003) when compared to 2R3RG patients. Patients with "median/high expression genotypes" demonstrated a better survival at 12 months (p=0.041) when compared to "low expression genotypes". Furthermore, 6 bp- carriers (p=0.006) showed a better survival at 12 months when compared to 6 bp+ homozygotes patients. When analyzing TYMS haplotypes, better survival at 12 months was observed for patients carrying haplotypes with the 6 bp- allele (2R6 bp-; p=0.026 and 3RG6 bp-; p=0.045). This is the first report that evaluates the three major TYMS polymorphisms in the therapeutic outcome of NSCLC in Portugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemotherapy regimens.

Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics.

TS is critical for providing the requisite nucleotide precursors in order to maintain DNA synthesis and repair. Furthermore, it is an important target for several drugs such as 5-fluorouracil and methotrexate. However, several mechanisms of resistance to TS inhibitors have been explained as linked to TYMS overexpression. Some authors have described the relationship between genetic polymorphisms on TYMS, in particular rs34743033, rs2853542 and rs34489327, with the development of several diseases and with the clinical response to drug therapy and/or survival. Nevertheless, the obtained results described in the literature are controversial, which has lead to a search strategy to understand the impact of these polymorphisms on molecular epidemiology and pharmacogenetics. With the progress of these scientific areas, early identification of individuals at risk of disease along with improvement in the prediction of patients' outcome will offer a powerful tool for the translation of TYMS polymorphisms into clinical practice and individualization of treatments.

Associação do anticorpo anticitrulina e gravidade da artrite reumatóide / Association of anti-cyclic citrullinated peptide antibody and severe rheumatoid arthritis

OBJETIVOS: Avaliar a associação do anticorpo antipeptídeo citrulinado cíclico (anti-CCP) com distintos parâmetros clínicos, sorológicos e radiológicos. MÉTODOS: Anti-CCP e fator reumatóide (FR) foram pesquisados no soro de 100 pacientes com artrite reumatóide (AR). A atividade da doença foi definida por meio de um índice combinado compreendendo cinco parâmetros: número de juntas inflamadas, número de juntas doloridas, rigidez matinal, escala visual analógica (EVA) de dor e velocidade de hemossedimentação (VHS). A capacidade funcional foi medida pelo índice HAQ (Health Assessment Questionnaire) e a classe funcional foi determinada mediante aplicação dos critérios revisados do American College of Rheumatology (ACR), de 1991. Erosão e pinçamento articular foram graduados pelo índice de Sharp modificado. A análise estatística empregou os testes do Qui-quadrado, Mann Whitney e Kruskal-Wallis. RESULTADOS: Nenhum dos dois anticorpos demonstrou associação significativa com atividade da doença, sexo, idade de início da doença, presença de nódulos subcutâneos e síndrome de Sjõgren. A média de idade foi significativamente menor nos pacientes com AR anti-CCP positivos. A positividade para o FR e anti-CCP foi maior nos pacientes com AR com menos de 50 anos em comparação com os pacientes com mais de 50 anos. A AR de início recente (< 2 anos) não se associou a uma maior prevalência de soropositividade para o anti-CCP e FR. O anti-CCP apresentou uma correlação positiva moderada com o FR. Houve uma correlação direta entre o anti-CCP e a VHS e a proteína C reativa (PCR). Houve também uma correlação direta entre o FR, a VHS e a PCR. A classificação funcional dos critérios revisados do ACR de 1991 não se associou a qualquer dos dois auto-anticorpos. O índice de HAQ não se correlacionou com a atividade da doença, duração da doença, positividade do FR e atividade medida pela PCR, mas associou-se nitidamente à positividade do anti-CCP e à atividade medida pelo...

OBJECTIVE: Evaluate the association of Anti-Cyclic Citrullinated Peptide Antibody (anti-CCP) with distinct clinic, serological and radiological parameters. METHODS: anti-CCP and rheumatoid factor (RF) were determined in the serum of 100 patients with rheumatoid arthritis (RA). Disease activity was defined by means of a combined index with five parameters: number of swollen joints, number of painful joints, morning stiffness, pain visual analogue scale (VAS), and erythrocyte sedimentation rate (ESR). Functional capacity was measured by (Health Assessment Questionnaire) HAQ index and the functional class was ascribed according to American College of Rheumatology criteria (1991). Articular erosion and narrowing were estimated by the modified Sharp's index. Statistical analysis was performed by chi-square, Mann-Whitney, and Kruskal-Wallis tests. A value of less 0.05 was considered significant. RESULTS: None of the two antibodies showed association with disease flare, gender, age in the time of diagnosis, secondary Sjõgren's syndrome or subcutaneous nodules. The mean age was significantly lower in RA patients with positive anti-CCP. The RF and anti-CCP positivity was higher in RA patients below 50 years old than patients above 50 years old. The early RA, up to 2 years of evolution, was not associated with a higher prevalence of anti-CCP and RF reactivity. Anti-CCP showed direct moderate correlation to RF and also direct correlation to ESR and CRP. FR reactivity showed direct correlation to ESR and CRP. Functional class showed no association with neither autoantibodies. HAQ index showed correlation with anti-CCP-positive patients and activity assessed by ESR, but did not show association with disease activity, disease duration, presence of the RF and activity assessed by ESR. Sharp's erosion and narrowing index showed association to presence of anti-CCP, but not with RF positive patients. CONCLUSIONS: Although anti-CCP displays good diagnosis...

Valor diagnóstico do anticorpo antipeptídeo citrulinado cíclico na artrite reumatóide / Diagnostic value of anti-cyclic citrullinated peptide antibody in rheumatoid arthritis

INTRODUÇÃO: a artrite reumatóide (AR) é considerada uma das doenças auto-imunes mais freqüentes, mas um teste viável e específico para seu diagnóstico não está disponível. OBJETIVOS: avaliar a eficiência diagnóstica de um novo teste comercial realizado pela técnica de ELISA (Immunoscan RA; EuroDiagnostica), que detecta o anticorpo antipeptídeo citrulinado cíclico (anti-CCP), para o diagnóstico da AR. MÉTODOS: anticorpo anti-CCP e fator reumatóide (FR) foram pesquisados no soro de 486 pacientes: 100 pacientes com AR e 386 controles, incluindo indivíduos normais, pacientes com outras doenças reumáticas e não-reumáticas, bem como pacientes com doenças infecciosas. Avaliação comparativa do desempenho diagnóstico dos testes foi feita mediante cálculo dos diversos índices diagnósticos e da curva ROC (receiver operator characteristic). A análise estatística foi feita utilizando os testes do qui-quadrado, exato de Fisher e Mann-Whitney. RESULTADOS: ao ponto de corte de 25 UI/ml, o anti-CCP apresentou sensibilidade de 68 por cento (IC 95 por cento, 57,8-76,8 por cento), especificidade de 97,7 por cento (IC 95 por cento, 95,5-98,8 por cento), valor preditivo positivo (VPP) de 88,3 por cento (IC 95 por cento, 78,5-94,2 por cento), valor preditivo negativo (VPN) de 92,2 por cento (IC 95 por cento, 89-94,5 por cento) e razão de verossimilhança (RV) de 29,2 por cento (IC 95 por cento, 15,1-56,4 por cento). Os pacientes com AR anti-CCP positivos apresentavam titulação média igual a 920,7 UI/ml (variação, 70,5- 2000 UI/ml). Pacientes não-reumatóides anti-CCP positivos apresentavam titulação média de 38,7 UI/ml (variação, 29,5-47,4 UI/ml). O desempenho do anti-CCP, avaliado através da curva ROC, foi superior ao do FR. O FR apresentou uma sensibilidade maior (91 por cento) e uma especificidade menor (78,8 por cento) do que o anti-CCP. Quando os dois anticorpos foram usados em conjunto, a especificidade foi de 99,5 por cento. CONCLUSÃO: o anti-CCP foi o...

INTRODUCTION: Rheumatoid arthritis (RA) is one of the most common autoimmune rheumatic diseases, but a specific and reproducible test for its diagnosis is still lacking. OBJECTIVES: To evaluate the diagnostic efficiency of a new commercial ELISA kit in detecting anti-cyclic citrullinated peptide antibodies (anti-CCP) for the diagnosis of RA. METHODS: Anti-CCP antibodies and rheumatoid factor (RF) were determined in the serum of 486 patients: 100 patients with RA and 386 controls, including healthy subjects, patients with other non-rheumatic and rheumatic disease, as well as patients with infections disease. Comparative evaluation of diagnostic performance of anti-CCP and RF was done by calculation the several diagnostic indexes and construction of the ROC (receiver operator characteristic) curve. Statistical analysis included chi-square, Fisher exact, and Mann-Whitney's test. RESULTS: At cutoff of 25 UI/ml, anti-CCP showed sensitivity of 68 percent (95 percent CI, 57,8-76,8 percent), specificity of 97,7 percent (95 percent CI, 95,5-98,8 percent), positive predictive value (VPP) of 88,3 percent (95 percent CI, 78,5-94,2 percent), negative predictive value (VPN) of 92,2 percent (95 percent CI, 89-94,5 percent) and likelihood ratios (LR) of 29,2 percent (95 percent CI, 15,1-56,4 percent). Anti-CCP-positive RA patients had a mean antibody concentration of 920,7 UI/ml (range, 70,5-2000 UI/ml). Anti-CCP-positive non-RA patients had a mean antibody concentration of 38,7 UI/ml (range, 29,5-47, 4 UI/ml). The diagnostic performance of anti-CCP, as estimated by the ROC curve, was superior to that of RF. RF had a higher sensitivity (91 percent) and a lower specificity (78,8 percent) than anti-CCP. When the two antibodies were used together, specificity was 99,5 percent. CONCLUSION: The anti-CCP testing presented the best diagnostic performance for RA and was the most specific test. It may be useful if performance concomitantly with RF in the diagnostic...