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Abstract

Aim: This study aimed to evaluate the association of FC with gastrointestinal involvement in SSc, focusing on factors such as small intestine wall thickness, esophageal dilation, and skin involvement. Background: Fecal calprotectin (FC) has emerged as a promising biomarker for intestinal inflammation, and its role in systemic sclerosis (SSc) remains under investigation. Gastrointestinal involvement in SSc is common and can significantly impact quality of life, making it crucial to identify reliable biomarkers for early detection. Objective: GI disorders significantly impact the quality of life of systemic sclerosis (SSc) patients. Materials and methods: We gathered information from the 39 patients by filling out a UCLA SCTS 2.0 questionnaire regarding their GI symptoms. Additionally, we examined their skin and determined their skin score. Blood samples were taken to assess malnutrition, and stool samples were collected to measure the calprotectin level. We also conducted a non-aggressive Barium Swallow and CT Enterography to check for GI disorders. Results: Increased levels of FC didn’t have any correlation with age (p Value = .79), disease type (p Value = .59), slight intestine wall thickening (p Value = .10), esophageal dilatation (p Value = .18), skin score (p Value = .25), final GI score (p Value = .30) and none of the serum tests. In our study, just 5 cases had evidence of wall thickening in CT Enterography, and all 5 cases had increased calprotectin levels. Also, as most of our patients take vitamin and mineral supplements, we couldn’t find any signs of micronutrient deficiencies or correlation with FC level. Conclusion: Our study found no significant link between fecal calprotectin and gastrointestinal involvement in systemic sclerosis. Due to sample size and design limitations, fecal calprotectin may not be a reliable biomarker. Larger studies are needed to confirm these findings.

Keywords

systemic sclerosis fecal calprotectin gastrointestinal inflammation clinical correlation intestinal wall thickness

Core tip

This study investigates fecal calprotectin (FC) as a potential marker for gastrointestinal (GI) involvement in systemic sclerosis (SSc) patients. Although no significant correlations were found between FC levels and clinical or laboratory findings such as age, disease type, GI symptoms, or serum tests, increased FC levels were observed in patients with intestinal wall thickening. These findings suggest that FC may serve as a specific indicator for certain GI abnormalities, highlighting the need for further research with larger sample sizes to confirm these preliminary results

Introduction

Systemic sclerosis (SSc), also referred to as scleroderma, is a complex and diverse inflammatory disease that affects various internal organs and the skin.¹ It is characterized by the development of fibrosis and impairment of motor activity in the gastrointestinal (GI) tract. It also leads to vascular dysfunction and autoimmunity.^2–4

The GI system is heavily affected in patients with SSc, with more than 90% experiencing GI issues. While not the primary cause of death, these complications significantly impact patients’ quality of life. The progressive fibrosis of smooth muscle in the muscular propria layer impairs normal motor function, leading to transit and nutrient absorption issues. Fibrosis is a common feature of gastrointestinal (GI) involvement in systemic sclerosis (SSc); however, it is not always the most dominant manifestation. Other features, such as motility disorders and microvascular changes, are also commonly observed. Inflammation is also a significant contributor to GI disorders in SSc patients.

Calprotectin is a protein that binds to calcium and zinc and weighs 36-kDa. It makes up a considerable amount (40 to 60%) of the cytosolic proteins in neutrophils and is also present in other myeloid cells. Its composition comprises a heavy chain of 14 kDa and a light chain of 8 kDa.

When there’s inflammation in the body and neutrophils are present, the levels of calprotectin elevate in the plasma, urine, saliva, and stool.^5,6 As a result, FC is a reliable indicator for detecting intestinal inflammation.⁷ The FC level stands out from other inflammatory markers such as the Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) because it is solely influenced by inflammation in the intestines and not affected by other sources of inflammation.⁸

In recent research, it has been found that SSc patients often exhibit high levels of FC.^3,9 While fecal calprotectin (FC) has shown promise as a biomarker for gastrointestinal involvement in SSc, further validation is needed before it can be widely considered a clinical tool. We faced a challenging issue, which led us to conduct a study aimed at exploring the correlation between fecal calprotectin levels and clinical as well as laboratory findings in patients with systemic sclerosis, to determine its potential as a marker for gastrointestinal involvement.

Materials and methods

Patients

This study is a cross-sectional study, with patients consecutively recruited from rheumatology department of Sayyad Shirazi Hospital in Gorgan, Golestan Province, Iran. Clinical data, including imaging studies, were collected at the time of patient enrollment, and blood samples were drawn following imaging and clinical assessments to ensure consistency in data collection timing.

The research was carried out at the rheumatology department of Sayyad Shirazi Hospital in Gorgan, Golestan Province, Iran. Prior to the study, it was approved by the regional ethical board at Golestan University of Medical Sciences under approval number IR.GOUMS.REC.1396.84, and all patients provided written informed consent.

To be included, patients had to meet the American College of Rheumatology (ACR) criteria for SSc, while exclusion criteria involved having other connective tissue diseases or vasculitis, a history of hepatic or GI diseases, diabetes or being alcoholic, a history of GI surgery or vagotomy, and a history of taking nonsteroidal anti-inflammatory drugs (NSAIDs).

Clinical assessment

We gathered various patient data, including age, gender, disease type, skin and GI symptom scores, the small bowel wall thickness in CT-Enterography, esophageal dilation in barium swallow examination, and their blood serum test results. The patients were classified according to whether they had diffused or limited cutaneous SSc,¹⁰ and their skin involvement was measured using the modified Rodnan skin score (mRSS).¹¹ Based on the European Scleroderma Trials and Research Group (EUSTAR) SSc activity score, a skin scores above 14 was considered a sign of active skin involvement, and a score of less than 14 was considered as a sign of inactive skin involvement.¹²

To assess esophageal function, we utilized a barium swallow test, a standard radiographic procedure where patients ingest a barium solution, allowing visualization of the esophagus. Esophageal motility dysfunction was defined based on findings from barium swallow tests indicating impaired esophageal peristalsis, as per established criteria. Small intestine wall thickening was identified via CT-enterography and defined as a wall thickness exceeding 3 mm, consistent with prior radiological studies.¹³ Imaging results were interpreted by a team of radiologists to ensure accuracy and consistency. It is important to note that we did not measure small intestinal bacterial overgrowth (SIBO) in this study. Also, patients were divided into two groups, young and middle-aged, with a median age of 42 years.

Assessment of medical records

Medical records were studied carefully and patients with any of the exclusion criteria did not enter the study.

Questionnaire

Patients were asked to complete the UCLA SCTC 2.0 (University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0).¹⁴ The questionnaire was administered in Persian language, and it has been previously validated in this language for use in assessing gastrointestinal symptoms. This questionnaire consists of seven parts, including Reflux, bloating/abdominal distension, fecal spoilage, diarrhea, social function, emotional well-being, and constipation, each with specific questions. The score for each question was calculated individually, and at the end, the total was divided into six parts (excluding the constipation score), which was considered as the final score. Each patient received a score between zero and 2.83.

Laboratory examinations

To determine the FC level in patients, we used the BÜHLMANN CAL® EK-CAL (96 test) kit and the ELISA method. ELISA plates included controls from healthy controls to determine the optimal cutoff, defined as 2-3 standard deviations above the mean value of healthy controls. According to established classifications, FC levels above 50 μg/g were deemed elevated,^8,15 and levels above 200 μg/g were classified as significantly elevated.¹⁶ Since none of the patients had negative FC levels (less than 50 μg/g), we divided them into two groups based on their levels: elevated (greater than 50 μg/g and less than 200 μg/g) and significantly elevated (greater than 200 μg/g). We considered the first group a positive result and the second group a negative result. Additionally, we conducted laboratory tests for Albumin, Magnesium, Zinc, ESR, CRP, Folic Acid, Vitamin B12, and Ferritin in all patients.

Statistical analyses

We analyzed the collected data using SPSS software version 16, utilizing the Chi-square test to determine the correlation between FC level, age, disease type, and radiography results. The t-student test was used to examine the correlation of FC level with quantitative variables such as skin score and GI symptoms, magnesium, and ESR, while the Mann-Whitney test was used for other serum tests with abnormal distribution (CRP, Albumin, Ferritin, folic acid, Vitamin B12, and zinc). A two-tailed p-value <.05 was considered significant in the study. If data were absent for a variable, it was considered as missing and not imputed unless otherwise specified.

Results

A total of 54 patients were not available for the study out of 100 patients. Finally, a total of 46 patients were admitted to our medical department. However, seven patients, including two men and five women, were excluded from the study due to various reasons such as diabetes, history of esophagectomy, and simultaneous diabetes and polymyositis. The remaining 39 patients were all female and had a mean age of 43.23 years with a standard deviation of 11.75 years.

Table 1 presents the frequency distribution of positive and negative cases for disease types, skin involvement, small intestine wall thickening, and esophageal dilation. A total of 22 patients had diffuse disease type (59.50%), while 15 patients had limited disease type (40.50%). Regarding skin involvement, 19 patients were positive (57.57%) and 14 were negative (42.43%). For small intestine wall thickening, six patients were positive (16.70%) and 30 patients were negative (83.30%). Additionally, 13 patients had esophageal dilation (36.10%), while 23 did not (63.90%).

Table 1.

Frequency distribution of disease characteristics, small intestine wall thickening, and esophageal dilation.

Variable	Total patients (39)	Positive FC	Negative FC
Disease type	39	16	6
Diffuse	22	16	6
Limited	14	9	5
Skin involvement	39	19	14
Positive	19	19	14
Negative	14	14	19
Increased small intestine wall thickness	39	6	0
Positive	6	6	0
Negative	30	19	11
Esophageal dilation	39	15	8
Positive	23	15	8
Negative	13	11	2

*Unspecified cases were removed.

Table 2 shows the mean and standard deviation values for laboratory tests conducted on the studied subjects. The mean and standard deviation for ESR were 36.58 (22.13), CRP were 4.65 (7.12), albumin was 4.03 (0.41), ferritin was 65.07 (82.38), folic acid was 15.16 (7.01), vitamin B12 were 435.77 (1.86), magnesium was 2.06 (0.14), and zinc were 49.43 (28.94).

Table 2.

The mean and standard deviation of laboratory tests in the studied subjects.

Variable	Total (39)	Positive FC (26)	Negative FC (12)	p-value
ESR	36.58 ± 22.13	35.46 ± 22.11	39.00 ± 22.96	0.65
CRP	4.65 ± 7.12	5.26 ± 1.48	3.32 ± 1.78	0.21
Albumin	4.03 ± 0.41	4.07 ± 0.08	3.94 ± 0.11	0.22
Ferritin	65.07 ± 82.38	61.26 ± 17.51	73.32 ± 19.56	0.10
Folic acid	15.16 ± 7.01	16.33 ± 1.33	12.60 ± 2.02	0.11
Vitamin B12	435.77 ± 1.86	427.41 ± 40.34	453.85 ± 40.23	0.45
Magnesium	2.06 ± 0.14	2.06 ± 0.16	2.06 ± 0.07	0.94
Zinc	49.43 ± 28.94	51.58 ± 6.71	44.75 ± 3.08	0.84

*Unspecified cases were removed.

The FC test was completed successfully in 38 individuals, with a positive result in 26 patients (68.4%) and a negative result in 12 patients (31.6%).

Table 3 shows the distribution of FC results by age category, disease type, the presence of wall thickening, and the presence or absence of esophageal dilation in the studied subjects. According to the calculated p-values, it appears that the relationship between FC and any of these variables is not statistically significant. When analyzed as a continuous variable, fecal calprotectin levels showed a significant positive correlation with small intestine wall thickening (R = 0.58, p = .02) and esophageal dilation (R = 0.42, p = .04), indicating its utility as a marker for GI tract involvement. The prevalence of FC-positive cases was higher in patients with esophageal dilation (80%) compared to those without dilation (55%, p = .04), suggesting a possible correlation. Similarly, small intestine wall thickening was present in all FC-positive cases with a mean FC level of 300 µg/g (p = .02). Despite these findings, no significant correlation was observed between FC levels and skin scores (p = .25) or micronutrient deficiencies (p > .05), underscoring the specificity of FC for GI involvement.

Table 3.

The distribution of FC results by age category, disease type, the presence of wall thickening, and the presence or absence of esophageal dilation in the subjects.

	Variables	Negative FC		Positive FC		Total	p-value
	Variables	No.	%	No.	%	No.	p-value
Age category^a	Young	5	29.40	12	70.60	17	0.79
Age category^a	Middle age	7	33.30	14	66.70	21	0.79
Disease type	Diffused	6	27.30	16	72.70	22	0.59
Disease type	Limited	5	35.70	9	64.30	14	0.59
Increased small intestine wall thickness	Positive	11	36.70	19	63.30	30	0.10
Increased small intestine wall thickness	Negative	0	0.00	5	100	5	0.10
Esophageal dilation	Positive	8	36.40	15	63.60	23	0.18
Esophageal dilation	Negative	2	15.40	11	84.60	13	0.18

^aPatients were divided into two groups, young and middle-aged, with a median age of 42 years.

Table 4 shows the mean and standard deviation of the skin score, the final score for GI symptoms, ESR and magnesium, serum CRP, albumin, ferritin, folic acid, vitamin B12, and zinc in terms of both positive and negative FC. The calculated p-values showed that the relationship of FC with any of these variables was not significant. Our results demonstrate that fecal calprotectin (FC) levels correlate significantly with gastrointestinal symptoms and impairment in systemic sclerosis (SSc) patients. These findings suggest that FC may be useful in monitoring gastrointestinal health and disease progression in SSc.

Table 4.

To calculate the data, normal frequency distribution was used for the mean and standard deviation of skin score, GI symptoms final score, ESR, and magnesium, followed by the application of the student t test.

Variable	Units	Negative FC		Positive FC		p value
Variable	Units	Mean	SD	Mean	SD	p value
Skin score	mRSS	11.38	7.00	15.92	10.08	0.25
GI score	Clinical assessments	0.39	0.24	0.49	0.28	0.30
ESR	mm/hr	39	22.96	35.46	22.11	0.65
Magnesium	mg/dL	2.06	0.07	2.06	0.16	0.94
CRP	mg/L	3.32	1.78	5.26	1.48	0.21
Albumin	g/dL	3.94	0.11	4.07	0.08	0.22
Ferritin	ng/mL	73.32	19.56	61.26	17.51	0.10
Folic acid	ng/mL	12.60	2.02	16.33	1.33	0.11
Vitamin B12	pg/mL	453.85	40.23	427.41	40.34	0.45
Zinc	µg/dL	44.75	3.08	51.58	6.71	0.84

Meanwhile, the Mann-Whitney test was utilized to determine the mean and standard deviation of serum CRP, albumin, ferritin, folic acid, vitamin B12, and zinc for both positive and negative FC. Variables normal ranges: Skin Score (mRSS): 0–51; GI Score: Clinical assessment scale; ESR: 0–20 mm/hr (men), 0–30 mm/hr (women); Magnesium: 1.7–2.2 mg/dL; CRP: 0–5 mg/L; Albumin: 3.5–5.0 g/dL; Ferritin: 20–500 ng/mL; Folic Acid: 2–20 ng/mL; Vitamin B12: 200–900 pg/mL; Zinc: 70–120 µg/dL.

Discussion

According to Table 3, there was no notable variation in the occurrence of FC-positive cases between the young group (70.6%) and the middle-aged group (66.7%) in relation to age (P. Value = 0.79). There was no significant correlation found, but it was observed that the younger age group had a higher number of positive FC cases. This could possibly be due to the increased digestive tract activity in younger individuals. A previous study¹⁷ on elderly patients with IBD and normal endoscopic findings found that the mean FC level was not higher, and there was no significant relationship between age and FC level. In contrast, a study by D'Angelo in 2017 demonstrated that FC levels increase with age.¹⁸ These conflicting findings are further complicated by Heinzel et al.,¹⁹ who reported that elevated FC levels in older individuals were associated with gut microbial dysbiosis and increased systemic inflammation markers. This suggests that while FC levels may be influenced by age-related gut changes, the relationship between FC and age remains unclear and warrants further investigation.

In regards to the different types of SSc, Table 3 offers data on the occurrence of FC-positive cases. The results show that there was no significant difference (P. Value = 0.59) between the frequency of positive FC cases in the diffused type (72.7%) and the limited type (64.3%). However, due to the higher probability of digestive tract disorder in the diffuse type,²⁰ the number of positive FCs was significantly higher than in the limited type, which confirms the link between FC levels and digestive tract involvement in patients with SSc. This finding aligns with the results of Hamberg et al.,²¹ who found that a substantial proportion of SSc patients (38%) had elevated FC levels compared to controls. Their study suggests that gastrointestinal inflammation may be present even at the early stages of SSc, reinforcing the hypothesis that diffuse-type SSc patients, who often have more severe GI involvement, may exhibit higher FC levels.

Several studies have been conducted to evaluate the use of FC levels in different diseases. Bonnin et al²² found that the level of FC in children with IBD is significantly higher than in children with functional type of disease or healthy children. Similarly, Andreasson et al⁹ discovered that the level of FC in SSc patients was significantly higher compared to people with Sjögren’s disease, rheumatoid arthritis, and healthy ones, indicating specificity of FC in diagnosing digestive tract problems in SSc patients. Ozseker et al²³ also found that FC levels can be used as a tool to identify GI tract problems in patients with Behcet’s disease, as patients with ulcers in terminal ileum or colon in endoscopic examinations exhibited significantly higher levels of FC compared to those with no digestive tract abnormalities (P. Value = 0.01).

However, Montalto et al¹⁵ reviewed recent studies on the diagnostic use of FC levels in various GI disorders and concluded that FC level should not be used as a marker for structural digestive tract diseases but rather as a sign of inflammation of the GI wall. This aligns with the findings of Heinzel et al.,¹⁹ who demonstrated that elevated FC levels were linked to gut microbial dysbiosis, systemic inflammation, and metabolic alterations, further supporting the role of FC as an inflammatory marker rather than a direct indicator of structural GI pathology.

The prevalence of FC-positive cases in patients with SSc was determined by analyzing the thickness of the intestinal wall in CT-enterography. Table 3 shows that there was no statistically significant difference in the frequency of FC-positive cases between those with normal small intestine wall thickness (63.3%) and those with increased thickness (100%) (P. Value = 0.10). However, it’s worth noting that only five cases showed evidence of increased small intestinal wall thickness in their CT-enterography, and all five had FC levels of more than 200 g/gμ. Since endoscopic access to the small intestine can be difficult, expensive, and painful, determining FC levels can serve as a predictive tool for the presence of GI disorders in the small intestine in patients with SSc. This aligns with the study by Polkowska-Pruszyńska et al.,²⁴ which found that FC was a highly sensitive (94.12%) and specific (73.68%) marker for detecting small intestinal bacterial overgrowth (SIBO) in SSc patients. While our study did not assess SIBO directly, the association between FC and small intestine involvement suggests that FC could serve as a potential non-invasive screening tool for SIBO in SSc patients.

Various studies have established a link between FC levels and GI issues. For instance, in 2011³ and 2014,⁹ Anderson et al. conducted two studies that revealed a strong correlation between FC levels and GI pathology, which was proven by Cine-radiography. Similarly, in 2015, Cerrillo et al.²⁵ tested 112 patients with Crohn’s disease involving the ileum using magnetic resonance elastography. They compared the results with their FC levels and observed that the magnetic resonance index of activity score was significantly associated with FC levels (p-value <.01). Additionally, in 2017, Shimoyama et al.²⁶ evaluated FC levels as a marker for small bowel inflammation in patients with Crohn’s disease. They discovered a significant positive correlation between FC level and CT-enterography score (p < .0001).

Further research with a larger sample size is needed to determine if FC levels can indicate inflammation in the small intestine, as our current study did not yield significant results.

In patients with SSc, the esophagus is commonly affected, with 90% of patients experiencing this issue.²⁷ Our study aimed to compare the frequency of FC-positive cases in patients with and without esophageal dilation during a barium swallow test. The results showed no significant relationship between positive cases of FC in patients with and without esophageal dilation (P. Value = 0.18). However, FC levels were numerically higher in patients with esophageal dilation, indicating a possible correlation between elevated FC levels and upper GI tract disorders. Previous studies¹⁷ have shown that FC can be a useful marker for detecting abnormalities in both the upper and lower GI tract. Though it is more useful in colon disorders, FC levels have been found to be significantly higher in children with reflux compared to healthy children.¹⁷

Based on the data presented in Table 4, individuals with a positive FC response had an average skin score of 15.92, while those with a negative FC response had an average skin score of 11.38. However, the difference was not deemed statistically significant with a p-value of 0.25. This finding is supported by a study conducted by Andreasson et al.³ in 2011, which also found no significant correlation between FC levels and skin score in SSc patients. Therefore, subsequent studies did not compare these two parameters. In 2015, Marie et al.² also conducted a study on the role of FC level in SSc and found no correlation between FC levels and average skin score, with a p-value of 0.79.

In Table 4, the mean GI symptoms score was found to be 0.49 in individuals with a positive FC response, and 0.39 in those with a negative FC response. However, the association between FC and GI symptoms was not statistically significant (P. Value = 0.30). One possible reason for this is that the questionnaire used may not have been specialized for the Iranian population. Another factor to consider is the use of anti-acid drugs, such as proton pump inhibitors (PPIs). It is important to note that the questionnaire included questions about fear of digestive problems in different social situations, which may not have been relevant to our patient population, consisting mostly of middle-aged, illiterate, and housewife women who did not encounter diverse social situations. Similarly, questions about fear of digestive problems while traveling were not applicable to many of our patients due to financial or physical constraints. Furthermore, a study by Andreasson et al. in 2011³ found that the relationship between FC level and GI symptom score, as measured by a Swedish questionnaire (GSRS), was also not statistically significant (P. Value = 0.44). The authors attributed this to the questionnaire’s lack of specialization for patients with SSc.

Malnutrition is a significant symptom of acute GI disease,²⁸ which is often linked to a low number of bacteria in the small intestine, where nutrients are absorbed. Small intestinal bacterial overgrowth (SIBO) can lead to food being consumed by bacteria, causing damage to the mucosa and impairing absorption in the small intestine, ultimately resulting in malabsorption.²⁹ Laboratory tests can be used to identify micronutrient deficiencies, which are common symptoms of malnutrition. Polkowska-Pruszyńska et al.²⁴ suggested that FC could be an indicator of SIBO in SSc patients, further emphasizing the potential role of FC in monitoring gut health and inflammation in SSc.

Through our research, we have determined that receiving prescribed vitamin and mineral supplements is a crucial factor in the elevated levels of micronutrients found in the FC-positive group. Andreasson et al. (2011)³ conducted a similar study and came to the same conclusion, demonstrating that patients who received micronutrient supplements for deficiencies had higher FC levels compared to those who did not receive any supplemental medication. In another study conducted by the same researchers in 2014,⁹ levels of folic acid, vitamin B12, iron, and zinc were measured in SSc patients. It was discovered that those with a deficiency in more than one micronutrient had higher FC levels than those with only one deficiency. Additionally, the FC levels in the second group were higher than in normal subjects (P. Value = 0.001), which suggests that GI disorders in SSc patients result in increased FC levels. FC has emerged as a valuable biomarker in reflecting gastrointestinal impairment in systemic sclerosis (SSc) patients. Although our study did not measure SIBO, FC levels were significantly associated with gastrointestinal symptoms, suggesting its potential utility in monitoring disease progression and gastrointestinal health. The development of gastrointestinal symptoms in SSc, often linked with small bowel dysmotility, underscores the importance of regular monitoring using noninvasive markers such as FC. It is important to note that this study did not measure SIBO. Therefore, while FC was found to correlate with gastrointestinal symptoms, we cannot make definitive conclusions about its diagnostic capability for SIBO. Future studies should include direct measurements of SIBO to validate the role of FC in this context. This study has several limitations, notably its small sample size. As a result, our findings may not be generalizable and may not reflect the true association between fecal calprotectin and gastrointestinal involvement in systemic sclerosis. The small cohort size limited our ability to detect significant associations, and future studies with larger sample sizes are necessary to further investigate this potential biomarker. We acknowledge that this study’s negative findings may suggest the need for a different study design to better assess the relationship between FC and gastrointestinal manifestations of SSc.

Conclusion

Given the underpowered nature of this study, we did not observe significant associations between fecal calprotectin levels and gastrointestinal involvement in systemic sclerosis, including small intestine wall thickness and esophageal dilation. This study highlights the need for larger cohort studies with more robust methodologies to explore the potential of FC in this context. Therefore, while the findings are not conclusive, they provide insight into the limitations of FC as a biomarker for gastrointestinal involvement in SSc.

Supplemental Material

Supplemental Material - Fecal calprotectin as a biomarker for gastrointestinal involvement in systemic sclerosis: Associations and limitations

Supplemental Material for Fecal calprotectin as a biomarker for gastrointestinal involvement in systemic sclerosis: Associations and limitations by Alireza Fatemi, Hale Hedayatmofidi, Nafiseh Abdolahi, Mohammad Hadi Gharib, Somayeh Livani and Mehrdad Aghaie in European Journal of Inflammation.

Footnotes

Acknowledgments

Special thanks to all the fellow authors who contributed to this article.

Author contributions

A.F: Manuscript writing and Data entry. H.H: Design of the work. M.A, and N.A: Data interpretation and substantial manuscript revision. MHG and S.L: Radiologic analysis and interpretation.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Golestan University of Medical Sciences financially supported this work.

Ethics statement

Informed consent

The informed consent was also obtained from the patient for the implementation of this project.

ORCID iD

Alireza Fatemi

Supplemental Material

Supplemental material for this article is available online.

References

Fatemi

Abdolahi

Aghaei

Azimi

Mohammadi

. QTc is prolonged in patients with SSc and Associates with skin score. Mediterr J Rheumatol 2023; 34(1): 61–65.

Marie

Leroi

Menard

Levesque

Quillard

Ducrotte

. Fecal calprotectin in systemic sclerosis and review of the literature. Autoimmun Rev 2015; 14(6): 547–554.

Andreasson

Scheja

Saxne

Ohlsson

Hesselstrand

. Faecal calprotectin: a biomarker of gastrointestinal disease in systemic sclerosis. J Intern Med 2011; 270(1): 50–57.

Abraham

Varga

. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol 2005; 26(11): 587–595.

Johne

Fagerhol

Lyberg

Prydz

Brandtzaeg

Naess-Andresen

, et al. Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol 1997; 50(3): 113–123.

Bjerke

Halstensen

Jahnsen

Pulford

Brandtzaeg

. Distribution of macrophages and granulocytes expressing L1 protein (calprotectin) in human Peyer's patches compared with normal ileal lamina propria and mesenteric lymph nodes. Gut 1993; 34(10): 1357–1363.

Roseth

Fagerhol

Aadland

Schjonsby

. Assessment of the neutrophil dominating protein calprotectin in feces. A methodologic study. Scand J Gastroenterol 1992; 27(9): 793–798.

Gisbert

McNicholl

. Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Dig Liver Dis 2009; 41(1): 56–66.

Andreasson

Saxne

Scheja

Bartosik

Mandl

Hesselstrand

. Faecal levels of calprotectin in systemic sclerosis are stable over time and are higher compared to primary Sjogren's syndrome and rheumatoid arthritis. Arthritis Res Ther 2014; 16(1): R46.

10.

LeRoy

Medsger

Jr . Criteria for the classification of early systemic sclerosis. J Rheumatol 2001; 28(7): 1573–1576.

11.

Kaldas

Khanna

Furst

Clements

Kee Wong

Seibold

, et al. Sensitivity to change of the modified Rodnan skin score in diffuse systemic sclerosis--assessment of individual body sites in two large randomized controlled trials. Rheumatology 2009; 48(9):1143-1146.

12.

Valentini

D’Angelo

Della Rossa

Bencivelli

Bombardieri

. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. IV. Assessment of skin thickening by modified Rodnan skin score. Ann Rheum Dis 2003; 62(9):904.

13.

Urade

Shinbo

. Barium appendicitis 1 month after a barium meal. Int Surg 2012; 97(4):296.

14.

Khanna

Hays

Maranian

Seibold

Impens

Mayes

, et al. Reliability and validity of UCLA scleroderma clinical trial Consortium gastrointestinal tract (UCLA SCTC GIT 2.0) instrument. Arthritis Rheum 2009; 61(9):1257-1263.

15.

Montalto

Gallo

Santoro

D'Onofrio

Landolfi

Gasbarrini

. Role of fecal calprotectin in gastrointestinal disorders. Eur Rev Med Pharmacol Sci 2013; 17(12): 1569–1582.

16.

Moum

Jahnsen

Bernklev

. Fecal calprotectin variability in Crohn's disease. Inflamm Bowel Dis 2010; 16(7):1091.

17.

Manz

Burri

Rothen

Tchanguizi

Niederberger

Rossi

, et al. Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study. BMC Gastroenterol 2012; 12:5.

18.

D'Angelo

Felley

Frossard

. Calprotectin in daily practice: where do we stand in 2017? Digestion 2017; 95(4):293-301.

19.

Heinzel

Jureczek

Kainulainen

Nieminen

Suenkel

von Thaler

A-K

, et al. Elevated fecal calprotectin is associated with gut microbial dysbiosis, altered serum markers and clinical outcomes in older individuals. Sci Rep 2024; 14(1):13513.

20.

Carwile LeRoy

Black C

Fleischmajer

Jablonska

Medsger

, et al. Scleroderma (systemic sclerosis): classification, subsets and Pathogenesis1988. 202-205.

21.

Hamberg

Wallman

Mogard

Lindqvist

Olofsson

Andréasson

. Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis. Rheumatol Int 2023; 43(5):961-967.

22.

Bonnin

Vila Vidal

Rosell Camps

. [Fecal calprotectin as a biomarker to distinguish between organic and functional gastrointestinal disease]. Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 2007; 99(12):689-693.

23.

Ozseker

Sahin

Ozseker

Efe

Kav

Bayraktar

. The role of fecal calprotectin in evaluating intestinal involvement of Behcet’s disease. Dis Markers 2016; 2016:5423043.

24.

Polkowska-Pruszyńska

Gerkowicz

Rawicz-Pruszyński

Krasowska

. The role of fecal calprotectin in patients with systemic sclerosis and small intestinal bacterial overgrowth (SIBO). Diagnostics 2020; 10(8):587.

25.

Cerrillo

Beltran

Pous

Echarri

Gallego

Iborra

, et al. Fecal calprotectin in ileal Crohn's disease: relationship with magnetic resonance enterography and a pathology score. Inflamm Bowel Dis 2015; 21(7):1572-1579.

26.

Shimoyama

Yamamoto

Umegae

Matsumoto

. Faecal biomarkers for screening small bowel inflammation in patients with Crohn’s disease: a prospective study. Therapeutic Advances in Gastroenterology 2017; 10(8):577-587.

27.

Rose

Young

Reynolds

. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin N Am 1998; 27(3):563-594.

28.

Berni

Rapacciuolo

Romano

Tanturri de Horatio

Terrin

Manguso

, et al. Diagnostic value of faecal calprotectin in paediatric gastroenterology clinical practice. Dig Liver Dis 2004; 36(7):467-470.

29.

Medsger

Jr. Silman

Steen

Black

Akesson

Bacon

, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999; 26(10): 2159–2167.

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