Diagnostic possibilities of fecal calprotectin use in patients with inflammatory bowel diseases during pregnancy
(literature review and clinical observations)
Uspenskaya Yu. B., Belogubova S. Yu.
FGAOU I. M. Sechenov First MSMU(Sechenov Univercity) Ministry of Health of Russia, Moscow (rector – Acad. Russian Academy of Sciences, Professor P. V. Glybochko)
Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic progressive inflammatory bowel diseases (IBD) of unknown etiology, characterized by a long progressive course with alternating periods of exacerbations and remission. Clinical assessment of symptoms, laboratory, endoscopic, radiological methods of diagnosis and morphological study are used to diagnose IBD, monitor their course and evaluate the response to therapy. To determine the severity of the inflammatory process in intestines are used, the estimated indices of clinical activity of UC and CD (the best index, index, Harvey-Bradshaw, Rakhmilevich, Mayo), summarizing the symptoms, clinical examination and nonspecific laboratory markers of inflammation. However, the use of indices of clinical activity in routine medical practice does not always objectively reflect the severity of inflammation of the intestinal wall mucosa. The use of endoscopic examination methods is associated with both technical difficulties and high cost and often poor patient tolerance. In this regard, the search continues for adequate markers of the inflammatory process, which would be easy to perform and interpret, as well as cost-effective with frequent re-determination. Such biomarkers of intestinal inflammation activity are various biological substances isolated from feces. Among them, calprotectin, lactoferrin, neopterin, hemoglobin, metalloproteinases, metal peroxidases, poly – morphonuclear elastase, M-2-pyruvate kinase, etc.the Greatest experience and evidence base have been accumulated in respect of fecal calprotectin (FC). Calprotectin was first described by Fagerhol et al. in 1980, Calprotectin is a calcium and zinc-binding protein consisting of two heavy and one light polypeptide chain. The main source of calprotectin are neutrophilic granulocytes, as well as monocytes and macrophages. Calprotectin is quite stable and can be stored in the feces at room temperature up to 7 days. Active inflammation in UC and CD is accompanied by the recruitment of immune cells from the bloodstream and their migration to the inflamed intestinal mucosa and its infiltration. Through the intestinal wall polymorphonuclear leukocytes penetrate into the intestinal lumen, and therefore calprotectin is determined in the fecal masses in concentrations directly dependent on the degree of infiltration of the intestinal wall. FC can be increased with a number of diseases: diverticular disease, infectious diarrhea, celiac disease, colon cancer, food Allergy, collagenous colitis, reaction “transplant against host”, iatrogenic (receiving proton pump inhibitors, nonsteroidal anti-inflammatory drugs after radiation therapy), etc. In clinical practice the definition of FC is used mainly for the diagnosis and differential diagnosis of IBD and irritable bowel syndrome (IBS), monitoring activity and effectiveness of treatment and predict reactivation of IBD.
Assessment of fecal calprotectin for the diagnosis of IBD activity and prediction of relapses
Currently, the aim of IBD therapy is not only the absence of symptoms of IBD, but also to achieve healing of the intestinal mucosa. Control of mucosal healing can be carried out during repeated endoscopic and histological studies, which, of course, is not always appropriate and feasible. In this regard, as an additional objective diagnostic method that reflects the degree of inflammation and healing of the mucous membrane, the definition of non-invasive markers, and, first of all, FC, is used. In patients with IBD, FC proved to be a reliable marker of inflammatory activity in the gut. In this case, the values of FC are more correlated with endoscopic and histological activity and slightly – with the clinical activity of UC and CD. The diagnostic value of this correlation is very high, because even in the absence of symptoms, a clinically implicit inflammatory process can continue, leading to the progression of intestinal damage. According to meta-analysis of 13 studies conducted in 2014, FC is recognized as a reliable marker of GCS activity. The possibility of using FC as a predictor of exacerbation of the GCS has been demonstrated in a number of works in recent years. Meta-analysis of 6 prospective studies demonstrated high specificity and sensitivity of this biomarker in predicting the reactivation of UC and CD (78% and 73%, respectively).
High rates of FC against the background of clinical remission of IBD are associated with a significant risk of exacerbation of IBD within the next 12 months. However, the informativeness of FC values is higher for UC and BC in the form of colitis or ileocolitis, and less for ileitis. A study by Louis et al. the concentration of FC over 300 µg / g is recognized as an independent risk factor for exacerbation of the disease. According to DeVos et al. FC proved to be the best predictor of UC reactivation in patients receiving infliximab therapy.
When evaluating FC every 4 months., its levels exceeding 300 mg / g, indicated the imminent occurrence of exacerbation. However, FC levels<40 mg / g confirmed deep remission of UC. The recently published results of the study by Kostas and et al. confirmed the high diagnostic value of determination of FC in patients with IBD for short-term prediction of reactivation of the inflammatory process (more than 261 mg/kg with AUC=0,901, the sensitivity of 87.2% and specificity of 85.3%, P<0.001) and mucosal damage (more than 174 mg/kg with AUC=0,956, sensitivity of 91.9 per cent, specificity of 87.2%, P<0.001) . At the same time, FC proved to be a more accurate predictor of exacerbation than CRP. However, the combined estimate of increasing the level of FC in excess of the upper acceptable bounds in combination with an increase in CRP significantly increases the specificity of predicting exacerbation of IBD (95,1% vs 85,3%) and determine endoscopic activity (100% vs. 87,2%). Thus, FC is a predictor of inflammatory process activation in the intestine, long before the appearance of nonspecific systemic markers of inflammation and clinical manifestations.
Colonoscopy, which is the gold standard in the diagnosis and evaluation of IBD activity, in addition to technical difficulties in the second half of pregnancy may be associated with an unjustified risk of complications in pregnant women. Radiation diagnostic methods associated with x-rays are associated with an increased risk of mutagenic and teratogenic effects. In this regard, taking into account the simplicity and non-invasiveness, the use of FC assessment in pregnant women is extremely promising.
However, until recently, it was not clear whether the level of FC changes during pregnancy, like nonspecific markers of inflammation. In recent years, a number of studies have been conducted to study the effect of pregnancy on the concentration and informativeness of FC and, consequently, the possibility of using it as an objective marker of inflammation in this period. In the work of Bálint et al. the absence of significant changes in the concentration of FC in feces in healthy women during all trimesters of pregnancy was confirmed. Thus, the average concentration of FC in the first trimester was 32.5 µg / g in women, 30.4 µg/g in the second trimester, 43.6 µg / g in the third trimester. In general, the average concentration of FC was 36.9 µg/g and did not differ from that in non-pregnant healthy women (p=0.99). In the same study, in pregnant women with active IBD, the mean concentration of FC was 877.9 µg / g, while in women with remission-210.7 µg / g.the level of FC was statistically significantly higher in pregnant women with active IBD than in pregnant women (p<0.001) and in non-pregnant healthy women (p<0.001). The results showed no significant difference between the concentrations of FC in pregnant patients with inactive phase of the disease, healthy pregnant women (p=0.99) and healthy non-pregnant women (p=0.99). Thus, these results confirm the informativeness of FC as a marker of GCS activity in pregnant patients. Similar data on the absence of changes in the informativity of the FC were obtained in a prospective study of Shit FC and et al., including 33 patients with CD and UC. The absence of interrelations between FC and clinical manifestations, albumin, ESR and CRP levels (p=0.285, p=0.986, p=0.327 and p=0.491, respectively) was noteworthy. Probably, this may be due to the above influence of pregnancy on the indicators of CRP, ESR and blood albumin. At the same time held Schweistein H. et al. the study, which included 57 pregnant patients with IBD, revealed a positive correlation between FC and Crohn's disease activity index (CDAI) (r=0.60) and Mayo index (r=0.77) . Inverse data on the informativeness of clinical activity indices (ICA) and their correlation with FC were obtained in a study published in 2017, which included 46 patients with IBD. The results of the study confirmed the preservation of the diagnostic informativeness of FC in pregnant patients in all trimesters of gestation and after childbirth. Clinically significant are the concentrations of FC over 250 µg/g. While the FC level did not correlate with indicators of JAS. The authors suggest that adaptive physiological changes during pregnancy can affect the information content of the IR. It is noteworthy that the level of CRP correlated with the indicators of FC only in the II trimester of pregnancy. The following clinical examples illustrate the possibilities of using FC assessment during pregnancy
Clinical observation 1
Patient, N., 29 years old. From the history it is known that the patient for 5 years suffers from Crohn’s disease in the form of severe ileocolitis with perianal lesions (perianal abscess) and the presence of hormonal resistance. During the last 2 years, the patient received combined therapy with genetically engineered biological drug (GIB) and thiopurine (infliximab and azathioprine), which allowed to achieve clinical, endoscopic and laboratory remission. This pregnancy occurred spontaneously and was unplanned. At the request of the woman, the pregnancy was prolonged. According to the current recommendations of international expert organizations (ECCO – European organization for the study of ulcerative colitis and Crohn’s disease) and the manufacturer’s instructions (MSD, USA), the use of infliximab is not contraindicated during pregnancy. In cases of pregnancy in patients receiving combined therapy with thiopurines and gibp, it is recommended to cancel thiopurines in order to reduce the risk of immunosuppression and infections in the newborn . This was the basis for discontinuation of azathioprine from early pregnancy. In the future, monthly control of laboratory markers of inflammation, including PC, CRP, biochemical and clinical laboratory parameters was carried out, infliximab therapy was continued according to the standard scheme. At 10 weeks of pregnancy, there was an increase in the level of FC to 790 µg / g with normal CRP and no clinical symptoms. At the gestation period of 12 weeks, the patient had bloating, bubbling, rapid semi-formed stool up to 3-4 times a day with blood admixture. Infectious causes of intestinal symptoms were excluded. In the survey, the level of FC was 1300 µg / g, the level of CRP remained within normal values. Reactivation of BC was regarded as a partial loss of response to gibp. Taking into account the presence of hormone resistance and severe course of CD in the patient’s history, it was decided to escalate the dose of infliximab (reducing the interval between injections to 6 weeks). After the correction of therapy, there was a rapid decrease in the severity of clinical manifestations and a gradual decrease in the level of FC. It is noteworthy that the process of normalization of FC level lagged far behind the positive dynamics of clinical manifestations. Given the high probability of reactivation of the inflammatory process in the intestine, the last infusion of infliximab was postponed for 30 weeks of pregnancy. The FC level at the time of the last administration of infliximab was 287 µg/g. In the period 38-39 weeks of gestation, taking into account obstetric indications (anatomically narrow pelvis) underwent a planned delivery by cesarean section. A full-term boy weighing 3450 g and 53 cm long was born. The newborn was evaluated on a scale of Apgar 8-9. Infliximab and azathioprine were resumed in the early postpartum period. At the request of the woman lactation was medically suppressed. This clinical observation demonstrates an increase in the FC index in a pregnant patient, ahead of the appearance of clinical signs of activation of CD against the background of partial loss of response to gibp, as well as its decrease as the activity of inflammation in the intestine after optimization of treatment. Thus, changes in the level of FC during pregnancy in this clinical case can be considered as a predictor of CD reactivation and an indicator of treatment effectiveness.
Clinical observation 2
The patient M., 25 years old, complained of pain in the left abdomen, frequent liquid stool up to 5 times a day with blood admixture. According to the anamnesis, the patient from the age of 21 suffers from ulcerative colitis, total form of damage, chronic recurrent course. During exacerbations, the patient received therapy with glucocorticoids, 5-ASA, antibacterial drugs with good effect. During the last 6 months. against the background of maintenance therapy with 5-ask drugs, clinical, endoscopic and laboratory remission was noted, against which pregnancy occurred. In connection with apprehension of adverse effects of 5-ASA, self-abolished by treatment with the period of 4-5 weeks of gestation. At the period of 7 weeks of pregnancy, the patient noted the appearance of abdominal pain, rapid liquid stool up to 3-4 times a day with an admixture of mucus and blood. Used treatment with drugs based on medicinal herbs without clinical effect. Three weeks later, she applied for medical help. During the laboratory examination, attention was paid to the increase in the level of FC to 1150 µg / g with a moderate increase in the level of CRP (6 mg/l), a decrease in the level of hemoglobin to 105 g/l and concentrations of iron and ferritin. Therapy with 5-ASA (4 g/day) was resumed.) with good clinical effect. 3 weeks after the start of therapy showed improvement in general condition, normalization of CRP, the reduction of FC to 750 µg/g. Given the improvement in the condition of the patient independently to reduce the dose of therapy to 5-ASA 1.5 g/day. After 2 weeks, there was a return of clinical symptoms (bloating, frequent unformed stool with blood). 5-ASA therapy was resumed in the previous dosage with a good clinical effect. In the subsequent for the duration of pregnancy was carried out on a monthly basis equal to FC. When normal FC values are reached after 2 months. the dosage of 5-ASA was reduced to a maintenance 2 g/day. For the period of further observation of pregnancy and 6 months. clinical and laboratory remission of UC persisted after delivery. In this clinical observation, discontinuation of maintenance therapy of UC resulted in reactivation of the inflammatory process in the intestine during pregnancy. Early reduction of the therapeutic dose of 5-ASA after clinical remission, despite the high rates of FC, indicating the preservation of the inflammatory process in the intestinal wall, led to increased activity of UC and the need for longer therapy with high doses of 5-ASA. Reducing the dose of 5-ASA after achieving clinical and laboratory remission with normalization of FC allowed to maintain remission of UC until the end of pregnancy and in the postpartum period.
The high diagnostic significance of FC in relation to the activity of the current inflammation in the intestine and the prediction of its reactivation in the presence of clinical remission of IBD are of great practical interest both in planning pregnancy and in determining the tactics of treatment of UC and CD at its occurrence. Given the high informativeness and noninvasiveness of the method of determination, PC is of greater diagnostic value in pregnant women than in patients with IBD as a whole. Taking into account the presented literature data, it seems appropriate for us to include the definition of FC in the algorithm of management of patients with IBD at the stage of pregravid preparation and during pregnancy. The detection of elevated FC indices during pregnancy planning even in the absence of symptoms of active IBD is an indication of the need to preserve or optimize the therapy of the disease and the expediency of delayed pregnancy planning for the period of achieving complete remission of IBD. When pregnancy occurs, it is often a question of stopping and limiting the therapy of IBD in an effort to reduce the drug load on the body of a pregnant woman. However, this is not always justified under the GCS. Clinical remission of UC and CD may not reflect the histological activity of the disease. For this reason, the unjustified discontinuation of subclinically active inflammatory therapy contributes to the development of exacerbation of the disease during pregnancy. During pregnancy, an endoscopic study to monitor the effectiveness of treatment of IBD in the vast majority of cases is not possible. For this reason, to control the activity of the disease and the effectiveness of treatment during pregnancy is justified by the dynamic definition of indicators of FC. The question of the possibility of reducing the doses of drug therapy or its strengthening in pregnant women should be solved taking into account not only the clinical picture, but also on the basis of the level of FC.
FC is an objective and sensitive marker of GCS activity during pregnancy. The dynamic control of FC at the stage of preparation for conception and during pregnancy allows to determine the most favorable period for planning pregnancy, to optimize therapy depending on the activity of the inflammatory process in the intestinal wall and to prevent the development of clinical relapses.
Uspenskaya Yu. B., Belogubova S. Y. “Coloproctology. Scientific and practical medical journal ” No 2 (64) 2018 p. 95-102