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Evaluation of serum prolidase level in children with Familial Mediterranean Fever

Egyptian Rheumatology and Rehabilitation volume 51, Article number: 37 (2024) Cite this article

Abstract

Background

FMF (Familial Mediterranean Fever) is the most prevalent autoinflammatory disease. It arises due to mutations in the pyrin-encoding MEFV gene. Prolidase, an enzyme culpable of splitting the bonds of proline-containing dipeptides, is essential for matrix remodeling, collagen turnover, and cell proliferation. It has a crucial role in inflammation.

Aim

To compare serum levels of prolidase between FMF children during the attack-free periods and healthy children and to correlate it with different FMF disease criteria and inflammatory marker, also to investigate if it can serve as a marker for subclinical inflammation.

Results

Forty-one children diagnosed with FMF and 41 sex and age-matched apparently healthy children as a control group were included in this study, serum prolidase was measured by ELISA. The mean ± SD serum level of prolidase among FMF patients was 0.6 ± 0.2 mU/ml × 104, while among the control group, it was 1.3 ± 1.4 mU/ml × 104, a statistically significant difference existed between both groups, p value = 0.001. The level of serum prolidase was not correlated with FMF severity score, inflammatory markers, and other FMF disease criteria.

Conclusion

Serum prolidase level was lower among FMF patients during the attack-free period than in the healthy control group, it was not correlated with disease severity and was not predictive of the presence of subclinical inflammation. Further studies are needed to highlight the role of serum prolidase in FMF children.

Background

Familial Mediterranean Fever (FMF) is the earliest described and most prevalent hereditary auto-inflammatory disease [1]. It is an autosomal recessive inherited disorder that is most widespread among Jews, Turks, Armenians, and Arabs. Recurrent episodes of fever, polyserositis, and erythema are its defining features [2]. MEFV, the FMF gene, codes for the protein pyrin and is situated on chromosome 16p13.3. [3]. The predominant site of pyrin expression is in white blood cells [4]. The activation of the inflammasome and processing of the pyrogenic cytokine interleukin (IL)-1ß depend on it. Also, it is entangled. in the process of caspase-1 activation and the release of active IL-1 as a component of the inflammasome complex's structure [5]. Subclinical inflammation persists and raises the potential for complications, such as anemia, cardiac disease, and amyloidosis [6]. Colchicine represents the treatment gold standard, which diminishes attack incidence and amyloidosis chance [7]. Subclinical inflammation was detected in some FMF patients despite regular administration of colchicine [8].

Prolidase is a manganese-dependent matrix metalloproteinase indispensable for collagen synthesis [9]. It is classified within the dipeptidase family and can cleave carboxyl-terminal proline or hydroxyproline from dipeptides and tripeptides [10]. It has been identified in plasma, leukocytes, erythrocytes, and fibroblasts and is essential for numerous pathological and physiological processes, including angiogenesis, cell proliferation, wound healing, and carcinogenesis [11].

Previous studies evaluated prolidase enzyme activity in chronic inflammatory diseases and showed that its activity increases due to the degradation of collagen [12]. According to Bozkurt et al., increased serum prolidase, angiogenesis, and inflammation may be associated with the pathogenesis of Behcet disease [13].

Bayram et al. found that, in comparison to healthy controls, serum prolidase enzyme concentrations were substantially higher in FMF patients with attack-free periods [14]. Eser et al. detected that serum prolidase enzyme activity was higher in FMF patients during the attack period than in FMF patients during the attack-free period and the healthy control [15].

Prolidase deficiency (PD) is an inherent error of immunity. That exhibits a variety of outcomes, such as intellectual disabilities, splenomegaly, difficult-to-resolve skin ulceration, dysmorphic features, and recurrent infections [16]. Inflammatory and autoimmune characteristics of PD include hypergammaglobulinemia with high titers of IgE, IgA, and associated autoimmune diseases such as SLE [17, 18] and rheumatoid arthritis [17].

Our study aimed to compare serum prolidase levels in children with FMF during the attack-free period with healthy children and to correlate its level with other acute phase reactants and different FMF disease variables and severity scores.

Patients and methods

This research included 41 children diagnosed with FMF, according to the Yalçinkaya et al. criteria [19], and 41 age- and sex-matched apparently healthy children as a control group, from August 2020 to March 2021. Patients were followed up at the Rheumatology Clinic, Specialized Pediatric Hospital, Faculty of Medicine, Cairo University. All patients were during the attack-free period (at least 2 weeks clinically free from the end of the last attack), below the age of 16 years, and did not have any concomitant rheumatological disease. FMF patients with symptoms and signs of infectious disease and those with any other chronic diseases were excluded from the study. The Ethical Committee of the Faculty of Medicine, Cairo University, Egypt, approved the study (MS 247–2020). The sample size was calculated based on a previous study by Bayram et al. [14] using PASS 2008.

Full history taking, including demographic data, age of onset of FMF, age at diagnosis, disease duration, FMF manifestations during illness course, daily dose of colchicine in mg, adherence to colchicine (patient was defined as adherent if no colchicine dose was missed in at least 6 months before the study), response to colchicine, was assessed according to the FMF 50 score [20]. International Severity Scoring Systems for FMF (ISSF) were used for assessing disease severity [21]. Full general and systemic examinations were done at the time of the study. Measurement of serum prolidase was done for both groups by using enzyme-linked immunosorbent assay technique (ELISA) using human Xaa-pro Dipeptidase/prolidase (PEDP) ELISA kit from Sino Gene Clon Biotech Co., Ltd. with Catalogue No. SG-00102. Laboratory investigations were done during the period of study for the FMF patients' group, including complete blood picture, ESR, CRP, BUN, creatinine, serum amyloid A, urine analysis, and albumin/creatinine ratio in urine. Urinary albumin/creatinine ratio was measured using the turbidimetric immunoassay method, and patients were instructed to avoid exercise before sample collection. Microalbuminuria was defined as loss of albumin in urine in the range of 30– < 300 mg/24 h. MEFV gene mutation results were obtained from patients’ files. Caregivers of all research participants or their children older than 12 years were informed of the research’s objectives, steps, and potential advantages. Upon obtaining informed consent from their guardians, participants were enrolled in the study.

The reporting of this study conforms to the strengthening of the reporting of observational studies in epidemiology (STORBE) guidelines [22].

Statistical analysis

Data were coded and entered using the statistical package for the Social Sciences (SPSS) version 26 (IBM Corp., Armonk, NY, USA). Data was summarised using mean, standard deviation (SD), median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were performed utilizing non-parametric Kruskal–Wallis and Mann–Whitney tests. The Chi-square (Χ2) test was performed to compare categorical data. The exact test was used when the expected frequency was less than 5. Correlations between quantitative variables were done using the Spearman correlation coefficient. P values equal to or less than 0.05 were considered statistically significant.

Results

This study included 41 FMF children and 41 healthy age and sex-matched children as a control group, the mean age of FMF patients was 10.26 ± 3.57 years, while the mean age of the control group was 11.1 ± 3.6 years. Among our FMF patients, 20 (48.8%) were males, and 21 (51.2%) were females, while among the control group, 15 (36.6%) were females, and 26 (63.4%) were males. Serum prolidase level was higher among the control group with a mean of 1.3 ± 1.4 mU/ml × 104 than the FMF patient group with a mean of 0.6 ± 0.2 mU/ml × 104 as shown in Table 1, and there was a statistically significant difference between both groups (p value = 0.001). Characteristics of our studied FMF patients are shown in Table 2; there was a family history of FMF in 34 (82.9%) of the studied cases. The mean age of onset of FMF symptoms was 5.51 ± 3.52 years, while the mean age at diagnosis was 6.78 ± 3.55 years, and the mean disease duration among FMF patients was 4.78 ± 2.76 years. The mean frequency of FMF attacks in the last 6 months was 6.02 ± 7.97. Fever was the most frequent manifestation during the illness history of FMF patients, affecting 41 (100%) of our cases, followed by abdominal pain and arthralgia, affecting 33 (80%) and 19 (24%), myalgia was the least common symptom among FMF cases, affecting 5% of our cases. A history of scrotal affection was detected in 3 (15%) of male FMF patients. According to the ISSF score, 12 (29.3%) had mild ISSF severity scores, 19 (46.3%) had intermediate scores, and 10 (24.4%) had severe scores, the mean ISSF score was 3.61 ± 1.88. All FMF patients were on colchicine treatment, and the mean colchicine dose among the studied group was 0.94 ± 0.54 mg/day. Regarding adherence to colchicine, 26 (63.4%) were adherent and 15 (36.6%) were not adherent. According to the FMF 50 score, 27 (56.8%) of our patients were good responders to colchicine. Laboratory investigations of FMF patients are displayed in Table 3. The mean serum amyloid A level among FMF patients was 22.65 ± 51.21 mg/L, with a range between 1 and 221 mg/L, and there was correlation between serum amyloid A with ESR (p value = 0.024) and CRP (p value = 0.004), but no correlations were found between SAA and ISSF score (p value = 0.630), albumin/creatinine ratio in urine (p value = 0.574), daily colchicine dose (p value = 0.878) and colchicine usage duration (p value = 0.198). There was no difference between colchicine adherent and colchicine non-adherent patients as regards SAA level (p value = 0.231). Twenty-four percent of FMF cases had above-normal serum amyloid A levels. ESR values were elevated in 28 (68.3%) FMF patients during the attack-free period, and the mean ESR level was 17.66 ± 12.73 mm/first hour. CRP was positive in 6 (14.6%) of FMF patients, and the mean of its level was 2.33 ± 4.94 mg/dl. The heterozygous gene mutation was the most common genotype among our patients 27 (65.9%), followed by the compound heterozygous and then the homozygous mutations with the following frequencies 11 (26.8%) and 3 (7.3%) respectively. V726A, M694I, and E148Q were the most common MEFV gene mutations, affecting 12 (29.3%), 9 (22%), and 22%, respectively. The mean urinary albumin/creatinine ratio among FMF patients was 13.50 ± 15.09 mg/gm. Three of our patients had microalbuminuria with levels of 35, 36.9, and 92.6 mg/g.

Table 1 Demographic criteria and serum prolidase level of the study groups
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Table 2 Characteristics of the Familial Mediterranean Fever (FMF) children
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Table 3 The laboratory findings of FMF patients included in our study
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There was no significant difference in prolidase levels between patients who experienced abdominal pain, chest pain, arthralgia, arthritis, myalgia, or vasculitis and those who did not exhibit these manifestations, as indicated by p values of 0.923, 0.826, 0.781, 0.835, 0.699, and 0.380 respectively.

Table 4 shows no correlation between serum prolidase level with the age of FMF onset (p value = 0.455), age of FMF diagnosis (p value = 0.537), disease duration (p value = 0.279), ISSF severity score (p value = 0.647), daily colchicine dose in milligram (p value = 0.339), colchicine usage duration (p value = 0.170), SAA (p value = 0.106) Fig. 1, albumin/creatinine ratio in urine (p value = 0.116), ESR (p value = 0.351), and CRP (p value = 0.591). There was no difference between colchicine adherent and colchicine non-adherent patients as regards serum prolidase level level (p value = 0.758).

Table 4 Correlation between serum prolidase level with demographic criteria, FMF disease criteria, and different laboratory markers in patients with FMF
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Fig. 1
figure 1

Correlation between serum prolidase level and serum amyloid A among the studied FMF patients

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Discussion

Prolidase is a unique enzyme that has great importance in collagen turnover, inflammation, and tissue fibrosis [9].

Our study reported a statistically significant difference between the FMF patients during the attack-free period and the control group regarding serum prolidase level, which was higher in the control group (p value = 0.001). Contrary to our results, Bayram et al. documented increased serum levels of prolidase in adult FMF patients, especially during the attack [14]. Parallel to our results, serum prolidase levels were lower among ankylosing spondylitis patients with active disease than patients with inactive disease and the healthy control group [23]. Also, rheumatoid arthritis patients exhibited decreased levels of serum prolidase than in healthy control groups [24]. It was suggested that serum prolidase levels were lower in adult patients with rheumatic diseases than in healthy controls due to inadequate collagen turnover and compromised bone quality [23]. FMF is a disease with periodic polyserositis, and there is no continuous tissue breakdown and collagen turnover such as chronic rheumatic diseases affecting joints and bones, this may explain why serum prolidase levels Among our FMF patients were not elevated, also our study included FMF patients during the attack-free period only.

We could not find further research that assessed serum prolidase levels among FMF patients, however, recent research focused on the relationship between serum prolidase activity and FMF. Eser et al., found that serum prolidase enzyme activity (SPEA), increased among FMF patients during the attack period, which may play a role in both pathogenesis and progression of complications caused by the inflammatory process [15]; however, this study did not evaluate serum prolidase levels.

This may suggest that serum prolidase is not a marker of subclinical inflammation of FMF during the attack-free period, but further long-term follow-up studies, including FMF patients during the attack, are required to evaluate its role during FMF attacks.

Our results did not show any correlation between serum prolidase level and age of FMF onset, age of diagnosis, disease duration, frequency of attacks during the last 6 months, FMF genotypes, different FMF gene mutations, colchicine usage duration, ISSF score, or different laboratory results.

A review of the literature revealed a role of serum prolidase in autoimmune and inflammatory diseases, it was noticed that serum prolidase was lower in diseases that affect bone turnover and diseases that limit the patients’ physical activity, which suggests that serum prolidase has a more critical role in bone turnover rather than inflammation. Still, we could not find studies that included children with FMF or other pediatric autoimmune or chronic inflammatory diseases.

ESR and CRP values were elevated in 68% and 15% of FMF patients during the attack-free period, respectively, which denotes persistent subclinical inflammation during this period.

Our patient’s mean ± SD of serum amyloid was 22.65 ± 51.21 mg/dl. This is similar to findings detected in previous Egyptian studies on FMF children, which detected high SAA, tow weeks after the last FMF attack, suggesting the persistence of subclinical inflammation even in the absence of an attack [25]. The regular assessment of SAA titer is crucial in managing FMF patients due to its superior sensitivity in identifying subclinical residual inflammation, even during attack-free periods, compared to CRP or ESR [23].

Microalbuminuria was detected among our FMF patients, with a mean ± SD of 13.5 ± 15.09 mg/gram. Very young children and those in the early phases of the disease may develop microalbuminuria [24]; this implies that the progression of amyloidosis is not influenced only by its duration [25]. This microalbuminuria needed to be studied prospectively, as we had only a single test during the time of the study, the test must be repeated after following instructions strictly to exclude false results.

The most frequent mutations among our patients were V726A, M694I, and E148Q, with the following frequencies: 29.3%, 22%, and 22%; this finding is similar to another Egyptian study which found that M694I and V726A were the most frequent FMF alleles among Egyptian FMF children [26]. A Turkish M694V and R202Q were the most prevalent mutations among FMF patients in Turkey's Inner Black Sea region, according to one study [27]. Heterozygous MEFV mutation occurred most frequently in our FMF patients, representing 65.9% of cases, followed by compound heterozygous mutation in 26.8% of cases then the homozygous mutation was detected in 7.3% of patients; this is in contrast to the results of Dinçer et al., who found homozygous mutations in 48.8% of their patients, heterozygous in 27.9% of patients [28]. Different genetic backgrounds among different populations could explain these differences. 82.9% of our patients possessed an FMF-positive familial history. This is more than the results obtained by Ates et al., in which a positive family history of FMF was 54.5% [29]. This may be related to the frequent occurrence of consanguineous unions among the Arabs, which increases the possibility of genetic diseases.

Fever affected 100% of our patients, another Egyptian study showed that abdominal pain was the most frequent symptom among the studied group, followed by vomiting the fever [30]. Clinical manifestations of FMF vary from one patient to another, influenced by gene penetrance and environmental and epigenetic factors [31].

Colchicine averts attacks and renal amyloidosis development [32]. All our patients were on colchicine treatment with a mean dose 0.94 ± 0.54 mg/day and a mean administration duration of 4.78 ± 2.76 years. Twenty-seven (65.9%) patients had a good response to colchicine, another study showed that 69.5% of FMF children had a good colchicine response. Different responses to treatment may be affected by the genetic background of the disease [33].

Despite several studies in recent years, there is much conflicting data on prolidase levels in diseases. Also, the studies investigating serum prolidase levels among FMF patients are few and uninformative and did not include the pediatric age group.

The controversial results among studies on serum prolidase levels in FMF patients are inconclusive and uninformative. Our study had certain limitations, such as the small sample size and the fact that we did not incorporate FMF patients during the attack period to study the level of serum prolidase during the attack in FMF children.

In conclusion, in view of our results, serum prolidase level was lower among FMF patients during the attack-free period than in the healthy control group and was not correlated with different disease criteria, disease severity, and inflammatory markers. The role of serum prolidase level in subclinical inflammation among FMF children needs further research and studies must be conducted with a larger sample size and should include patients both during the attack and the attack-free period.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ELISA:

Enzyme-linked immunosorbent assay

FMF:

Familial Mediterranean Fever

MEFV:

Mediterranean fever

PD:

Prolidase deficiency

SAA:

Serum amyloid A

SLE:

Systemic lupus erythematosus

SPEA:

Serum prolidase enzyme activity

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Acknowledgements

We thank all patients included in this study.

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The authors received no specific funding for this work.

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Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, Cairo University, Giza, Egypt

    Iman Khaled Eyada & Hend Mohamed Abu Shady

  2. Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Giza, Egypt

    Walaa Abdelfattah

  3. Alharam hospital, Ministry of Health, Giza, Egypt

    Ahmed Mohamed Naguib

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  1. Iman Khaled Eyada
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Contributions

AN contributed to the gathering and analysis of participants’ data. HA contributed to the clinical assessment of cases, interpretation of results, and writing of the research. WA performed the laboratory tests and analysis of data. IE contributed to the analysis of data and reviewing of research. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Hend Mohamed Abu Shady.

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The Pediatric Department Committee for Post-Graduate Studies and Research, Faculty of Medicine, Cairo University, Egypt, approved the study. Informed consents were obtained from the participants’ legal guardians.

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Eyada, I.K., Abdelfattah, W., Naguib, A.M. et al. Evaluation of serum prolidase level in children with Familial Mediterranean Fever. Egypt Rheumatol Rehabil 51, 37 (2024). https://doi.org/10.1186/s43166-024-00269-2

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