Fecal Dipeptidyl Peptidase-4: An Emergent Biomarker in Inflammatory Bowel Disease.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD). METHODS: We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed. RESULTS: When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464-7,816] vs 2,104 [630-2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559-1,682] vs 7,814 [2,555-7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559-1,420] vs 7,544 [4,531-7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58-0.94, P = 0.015) and 0.80 (95% CI 0.68-0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63-1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD. DISCUSSION: Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression.

The Role of Dipeptidyl Peptidase 4 as a Therapeutic Target and Serum Biomarker in Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: The roles dipeptidyl peptidase 4 (DPP4), aminopeptidase N (APN), and their substrates in autoimmune diseases are being increasingly recognized. However, their significance in inflammatory bowel diseases (IBD) is not entirely understood. This systematic review aims to discuss the pathophysiological processes related to these ectopeptidases while comparing findings from preclinical and clinical settings. METHODS: This review was conducted according to the PRISMA guidelines. We performed a literature search in PubMed, SCOPUS, and Web of Science to identify all reports from inception until February 2020. The search included validated animal models of intestinal inflammation and studies in IBD patients. Quality assessment was performed using SYRCLE's risk of bias tool and CASP qualitative and cohort checklists. RESULTS: From the 45 included studies, 36 were performed in animal models and 12 in humans (3 reports included both). Overall, the methodological quality of preclinical studies was acceptable. In animal models, DPP4 and APN inhibition significantly improved intestinal inflammation.Glucagon-like peptide (GLP)-1 and GLP-2 analogs and GLP-2-relase-inducing drugs also showed significant benefits in recovery from inflammatory damage. A nonsignificant trend toward disease remission with the GLP-2 analog teduglutide was observed in the sole interventional human study. All human studies reported an inverse correlation between soluble DPP4/CD26 levels and disease severity, in accordance with the proposal of DPP4 as a biomarker for IBD. CONCLUSIONS: The use of DPP4 inhibitors and analogs of its substrates has clear benefits in the treatment of experimentally induced intestinal inflammation. Further research is warranted to validate their potential diagnostic and therapeutic applications in IBD patients.

Serum Dipeptidyl Peptidase 4: A Predictor of Disease Activity and Prognosis in Inflammatory Bowel Disease.

BACKGROUND: Serum dipeptidyl peptidase 4 (DPP-4) has drawn particular interest as a biomarker in inflammatory bowel disease (IBD), as this protease inactivates several peptides that participate in the inflammatory cascade. METHODS: Two prospectively recruited cohorts consisting of 195 patients (101 had Crohn's disease [CD] and 94 had ulcerative colitis [UC]) were evaluated using clinical indexes and followed up to assess for treatment escalation. Sixty-eight patients underwent endoscopic evaluation at baseline. In the second cohort of 46 biologically treated patients, treatment response was assessed. Serum DPP-4, C-reactive protein (CRP), and fecal calprotectin levels were quantified at baseline and during follow-up. RESULTS: Median DPP-4 levels were significantly lower in active IBD patients when compared with remitters (CD: 1043 [831-1412] vs 1589 [1255-1956] ng/mL; P < 0.001; UC: 1317 [1058-1718] vs 1798 [1329-2305] ng/mL; P = 0.001) and healthy controls (2175 [1875-3371] ng/mL). In fact, DPP-4 was able to distinguish clinical and endoscopic activity from remission, with areas under the curve (AUC) of 0.81/0.93 (CD) and 0.71/0.79 (UC), along with the need for treatment escalation, with comparable AUCs of 0.79 (CD) and 0.77 (UC). Furthermore, DPP-4 levels were higher in responders to treatment and more pronounced among UC (1467 [1301-1641] vs 1211 [1011-1448] ng/mL; P < 0.001) than CD patients (1385 [1185-1592] vs 1134 [975-1469] ng/mL; P = 0.015). CONCLUSIONS: Our results suggest that serum DPP-4 can be used as a noninvasive biomarker of IBD activity and biological treatment response and a predictor of treatment escalation, particularly when combined with other biomarkers.

A Systematic Review on Infliximab and Adalimumab Drug Monitoring: Levels, Clinical Outcomes and Assays.

BACKGROUND: Immunogenicity to therapeutic proteins has been linked to loss of response by a large percentage of patients taking anti-tumor necrosis factor-alpha agents. Drug monitoring can be extremely useful, allowing physicians to adjust the therapeutic scheme individually. This article aims to systematically review the published data with respect to cutoff levels of infliximab (IFX) and adalimumab (ADA) and relate them to the methodology adopted for quantification of IFX and ADA levels and clinical outcomes. METHODS: The PubMed database was searched to identify studies focusing on the association between IFX or ADA cutoff levels and clinical outcomes in patients with inflammatory bowel disease. RESULTS: Of the 1654 articles initially selected by queries, 20 were included. A receiver operating characteristic curve analysis was performed to identify cutoff levels of IFX or ADA that correlated with a clinical outcome, but only 6 studies performed the same analysis for antidrug antibody levels. Cutoff levels were different between studies. The methodology chosen for level quantifications, clinical outcomes, and sample size and characteristics were also different. Nevertheless, measurement of drug levels should be performed during maintenance, and with loss of response, with persistent high levels of C-reactive protein, and when mucosal lesions are still present. In these scenarios, drug and antidrug levels were correlated with clinical outcomes. CONCLUSIONS: Concerning drug levels monitoring any methodology is adequate. With respect to antidrug antibody levels, it will be necessary to define a gold standard method or to establish different cutoff levels for different methodologies.

Indolent systemic mastocytosis limited to the bone: a case report and review of the literature.

CONTEXT Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. Its clinical course has a wide spectrum, ranging from indolent disease, with normal life expectancy, to highly aggressive disease, associated with multisystemic involvement and poor overall survival. The aim of this study was to report a case of indolent systemic mastocytosis, focusing on the diagnostic challenges, with a review of the literature. CASE REPORT A 79-year-old Caucasian woman with osteoporosis was evaluated at the Emergency Department because of complaints of low back pain. Before this, she had consulted an orthopedist and had undergone some imaging examinations, namely a bone scan that revealed a "superscan" pattern. Due to her pain complaints and these test results, the patient was admitted to the Department of Internal Medicine. After undergoing several analytical tests and some additional imaging examinations to rule out some important differential diagnoses, she then underwent bone marrow biopsy, which made it possible to identify indolent systemic mastocytosis. CONCLUSION Systemic mastocytosis is a rare entity that is difficult to diagnose. Its symptoms are often unspecific and frequently ignored. Skeletal changes may be the first and only manifestation of the disease and in some cases, like this one, the diagnosis is made only after histological examination. The key point for the diagnosis is to contemplate the possibility of systemic mastocytosis.

Indolent systemic mastocytosis limited to the bone: a case report and review of the literature / Mastocitose sistemica indolente restrita ao osso: um relato de caso e revisao da literatura

CONTEXT Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. Its clinical course has a wide spectrum, ranging from indolent disease, with normal life expectancy, to highly aggressive disease, associated with multisystemic involvement and poor overall survival. The aim of this study was to report a case of indolent systemic mastocytosis, focusing on the diagnostic challenges, with a review of the literature. CASE REPORT A 79-year-old Caucasian woman with osteoporosis was evaluated at the Emergency Department because of complaints of low back pain. Before this, she had consulted an orthopedist and had undergone some imaging examinations, namely a bone scan that revealed a “superscan” pattern. Due to her pain complaints and these test results, the patient was admitted to the Department of Internal Medicine. After undergoing several analytical tests and some additional imaging examinations to rule out some important differential diagnoses, she then underwent bone marrow biopsy, which made it possible to identify indolent systemic mastocytosis. CONCLUSION Systemic mastocytosis is a rare entity that is difficult to diagnose. Its symptoms are often unspecific and frequently ignored. Skeletal changes may be the first and only manifestation of the disease and in some cases, like this one, the diagnosis is made only after histological examination. The key point for the diagnosis is to contemplate the possibility of systemic mastocytosis. .

CONTEXTO A mastocitose sistêmica é definida como um distúrbio clonal do mastócito e suas células precursoras, sendo atualmente classificada como uma neoplasia mieloproliferativa. Seu curso clínico tem um espectro alargado, variando desde a doença indolente caraterizada por uma sobrevida normal, até a doença altamente agressiva associada a um envolvimento multissistêmico e a uma sobrevida reduzida. Este artigo reporta um caso de mastocitose sistêmica indolente, focando as principais dificuldades diagnósticas e fazendo uma revisão sistematizada da literatura. RELATO DO CASO Mulher de 79 anos, caucasiana, com antecedentes de osteoporose, foi avaliada no Serviço de Urgência por queixas de dor lombar. Antes disso, a doente havia consultado um ortopedista e realizado alguns exames de imagem, nomeadamente uma cintilografia óssea, que revelou um padrão em “superscan”. Em virtude de suas queixas álgicas e dos resultados dos estudos efetuados, foi internada no Departamento de Medicina Interna. Depois de realizados vários estudos analíticos e exames de imagem suplementares para excluir algumas importantes hipóteses de diagnóstico, a doente fez uma biópsia de medula óssea que permitiu identificar uma mastocitose sistêmica indolente. CONCLUSÃO A mastocitose sistêmica é uma entidade rara e difícil de diagnosticar. Os seus sintomas são muitas vezes inespecíficos e frequentemente ignorados. As alterações esqueléticas podem ser as primeiras e as únicas manifestações e, em certos casos, como este, o diagnóstico só pode ser feito após exame histológico. O mais importante para o diagnóstico é contemplar a hipótese de estarmos perante uma mastocitose sistêmica. .