Introduction

Familial Mediterranean Fever (FMF) is the most common hereditary monogenic auto-inflammatory disease, characterized by recurrent, self-limited episodes of fever and sterile inflammation of serous membranes. FMF is caused by mutations in the Mediterranean fever gene that encodes pyrin (also known as Marenostrin), which is essentially responsible for the regulation of apoptosis, cytokines, and inflammation [1].

The diagnosis of FMF is still based on clinical criteria since there is no specific diagnostic test. Tel Hashomer criteria are widely used for diagnosis of FMF [2].

The treatment of patients with FMF is aimed at suppressing the inflammation. Colchicine, an anti-inflammatory drug, is the first-line therapy to treat pain and to prevent amyloidosis in FMF; it can be used safely in pregnancy [3].

Studies suggest that inflammation persists even in attack-free, asymptomatic periods in FMF patients as shown by high levels of acute-phase proteins, cytokines, and inflammation-induced proteins [4].

Systemic inflammation can be measured by using a variety of biochemical and hematological markers. Recent findings indicate that measuring blood cell subtype ratios, such as the neutrophil to lymphocyte ratio (NLR), the platelet to lymphocyte ratio (PLR), and the lymphocyte/monocyte ratio (LMR), might provide prognostic and diagnostic clues to diseases related to chronic low-grade inflammation [5, 6]. Mean platelet volume (MPV) and platelet distributed width (PDW) are other examples of noninvasive biomarkers that can be easily tested [7,8].

In this study, we aim to investigate the potential of simple blood parameters including NLR, PLR, LMR, PDW, and MPV as emerging inflammatory markers to identify chronic inflammations during symptom-free periods in a group of pregnant patients with FMF. We also aim to investigate whether pregnant patients with FMF have an increased risk for perinatal complications.

Material and Method

This prospective case–control study was conducted between December 2014 and August 2015. Local Institutional Review Board approved the study and the universal principles of the Helsinki Declaration were applied. All patients provided written informed consent.

The diagnosis of FMF was made according to the Tel Hashomer criteria. The definitive diagnosis of FMF was made when two major criteria or one major and two minor criteria were present. The major criteria are: 1- recurrent febrile episodes accompanied by serositis, 2- AA type amyloidosis without apparent predisposing disease, and 3- favorable response to colchicine test. Minor criteria are: 1- recurrent febrile episodes, 2- erysipelas-like skin lesions, and 3- diagnosis of FMF in a first-degree relative [2].

All of the patients had Turkish ethnicity determined by country of origin. Of these, the women with FMF were already on colchicine treatment in appropriate doses to prevent attacks (1-2 mg daily). Proteinuria, suggestive of renal amyloidosis, was excluded on the basis of repetitive urine testing. Patients with any of the following criteria were not eligible to participate in the study: multiple pregnancy, detection of fetal anomalies by USG, and the history of any other systemic diseases.

The pregnancies of sixty patients diagnosed with FMF were followed during the study period at our hospital. A total of 27 patients with FMF were excluded from the study:2 had concomitant connective tissue diseases, 1 had diabetes mellitus, 2 had multiple pregnancies, 2 had IVF pregnancy, and 20 were late (after 14th weeks of gestation) registration (Figure 1). Two of the patients were later excluded from the study due to noncompliance and missing data.

A total of 65 consecutive singleton pregnancies who conceived spontaneously, 33 with FMF and 32 healthy women, were followed from the first trimester to the end of the pregnancies.

All of the patients were examined for infection, routine urine cultures were obtained, and body temperatures were measured. Patient with any signs and symptoms of active infection, (pain, fever, or vaginal discharge), were excluded from the study. None of the patients or controls had a multiple pregnancy, active labor, or pre-existing chronic systemic disease.

The diagnosis of preeclampsia was based on a systolic blood pressure of ≥140 mmHg or diastolic blood pressure ≥90 mmHg, measured twice in four-hour intervals while resting, after the 20th gestational week, as well as 300 mg/dL proteinuria detected in a 24-hour urine sample [9]. Preterm birth was defined as delivery before 37 weeks of pregnancy were completed. The diagnosis of fetal growth restriction was made when estimated fetal weight was below the tenth percentile and was associated with abnormal fetal Doppler parameters, with low birth weight defined as <2500 gram and very low birth weight as <1500 gram [10].

Blood samples for biochemical analyses (high-sensitivity C-reactive protein (hs-CRP), fibrinogen) and a complete blood count (CBC) were obtained at 11-13 weeks and at 16-19 weeks after detailed examination.

All CBC analyses were conducted in the central hematology laboratory of the hospital using a Gen-S automated analyzer (Beckman Coulter, High Wycombe, UK). NLR and PLR values were calculated by dividing the absolute neutrophil and platelet counts, respectively, by the absolute lymphocyte counts. LMR value was calculated by dividing the absolute lymphocyte by the absolute monocyte count. Blood samples were taken in standardized, EDTA containing tubes. Measurements were completed within one hour of blood sampling in order to avoid the EDTA-induced platelet swelling with time. Plasma concentrations of hs-CRP were determined with a Tinaquant CRP (Latex) high-sensitive particle-enhanced immuno turbidimetric assay on a Roche Modular P analyzer (Roche kit; Roche Diagnostics) according to manufacturer instructions. Minimum detectable concentration of hs-CRP was 1×10−5 mg/L. All samples were assessed in duplicate.

Maternal characteristics and levels of each participant, such as age, parity, body mass index (BMI), hs-CRP, fibrinogen, and CBC results, were recorded at first and second trimester. The perinatal outcome parameters, including gestational age at delivery, mean birth weight, mode of delivery, preterm delivery, preeclampsia, fetal loss, 5-minute Apgar score, and neonatal intensive care unit admission, were also assessed.

The statistical analyses were performed using IBM SPSS Statistics version 15 (IBM Corp., Armonk, NY). Normal distribution of data was assessed using the Kolmogorov–Smirnov test. Continuous and normally distributed variables were presented as mean ± standard deviation (SD) and intragroup differences were investigated using one-way analysis of variance. The data were summarized as mean ± standard deviation and median (minimum–maximum). Continuous variables were examined using Kruskal–Wallis tests if the data were not normally distributed. Categorical variables were expressed as number (percentage). Proportions were compared with Fisher’s exact test or the chi-square test where appropriate. Pearson’s correlation analysis was used to study the correlations between measurements. A two-sided p value <0.05 was considered statistically significant.

Results

Of the 60 patients diagnosed with FMF who were followed during the study period, 33 (55%) were enrolled in the study. The demographic characteristics of the groups are presented in Table 1. Maternal age, parity, and BMI were comparable between the groups. The duration of FMF during pregnancy was 7.1 ± 2.5 years in the study group and all of them were under treatment with colchicine 1.5-2 g daily.

Some inflammation related markers (obtained when all participants were asymptomatic) in both the FMF and control groups are shown in Table 2. While the mean WBC, NLR, PLR, PDW, fibrinogen, and LMR values were comparable between the groups, the mean hs-CRP levels were significantly higher and MPV values were significantly lower in the FMF group when compared with the control group at both the first and second trimesters.

There were no significant differences in mode of delivery (p=0.65). No differences in preterm delivery (p=0.73), preeclampsia (p=1), low Apgar scores (p=1), and NICU admission (p=1) were found between the groups. There were no cases of fetal chromosomal anomaly or perinatal mortality in either of the groups. The comparison of the perinatal outcomes of the FMF and control groups is presented in Table 3.

In correlation analysis, there was a significant negative correlation between hs-CRP levels with MPV at second trimester (r= -0.375 p=0.003).

Discussion

The main observation of this study is the identification of the potential role of novel inflammatory markers including NLR, PLR, LMR, and MPV. We found significantly higher serum hs-CRP and lower MPV levels in patients with FMF during the asymptomatic and attack-free period when compared to the controls at both first and second trimester. Indeed, in this study, we showed a negative correlation between MPV and m-CRP.

The attacks of FMF that are caused by neutrophil activation are typically accompanied by leukocytosis and elevation of CRP, fibrinogen, and other inflammatory parameters [4]. Colchicine is one of the oldest known drugs used for prophylaxis of FMF attacks and the prevention of the development of amyloidosis. Its anti-inflammatory mechanism differs from the other anti-inflammatory agents like nonsteroidal anti-inflammatory drugs and glucocorticoids. Instead of being involved in the arachidonic acid pathway, colchicine promotes microtubule depolymerization leading to cytoskeletal changes through cell mitosis, exocytosis, and neutrophil motility. Colchicine not only inhibits neutrophil chemotaxis and the production of interleukin-1, but also down-regulates the tumor necrosis factor alpha-receptors [1-3]. Moreover it has been shown that subclinical inflammation characterized by overproduction of hs-CRP and the other acute-phase reactants persists during remission period in FMF patients. Growing data suggests that colchicine decreases the levels of subclinical inflammation markers in FMF [4]. Indeed previous studies suggested that colchicine use suppresses platelet activation [11,12].

MPV, that universally available routine blood count by automated hemogram, is suggested as an indicator of platelet activation and reactivity that have also been associated with inflammation. Compared to lower platelets, higher platelets have larger granules; they aggregate more rapidly with collagen and increased thromboxane A2synthesis, and they show increased expression of P-selectin, glycoprotein IIb/IIIa and fibrinogen receptors [7].

In previous studies, the MPV levels were measured in patients with FMF. There were contradictory results in the literature. Coban et al. showed significantly higher MPV levels in attack-free periods of FMF patients when compared the healthy participants. They also found a negative correlation between MPV levels and the duration of colchicine treatment, and a positive correlation with delay of diagnosis. They suggested that patients with FMF tend to have increased platelet activation. Therefore, MPV level has been suggested as an index of the comprehensive inflammatory status of the body [13]. However Abanonu et al. reported no statistically significant difference between the FMF patients and the control groups in terms of MPV. They hypothesized that this result may be an effect of the colchicine on platelet function [14]. In another well-designated study, Sahin et al. reported decreased values of MPV in FMF patients during attack and attack-free periods than in healthy subjects [15]. This finding supported our study. We showed lower MPV levels in pregnant patients with FMF during attack-free periods compared to the healthy patients. Since all of our FMF patients had already been on regular colchicine therapy on admission, we admit, at least theoretically, that the anti-inflammatory and potential effects of colchicine on platelets could have altered our results.

Although the cause is not clear, some studies in the literature have shown that the prevalence of preterm births is higher in FMF [16,17]. It has been suggested that FMF is an independent risk factor for preterm delivery [16]. But others reported favorable pregnancy outcomes in patients with FMF treated with colchicine before and after pregnancy [18].

It is difficult to determine an actual cause because preterm birth is a multifactorial pregnancy complication. It has been difficult to determine the risk factors involved in a preterm birth due to various triggers that lead to spontaneous or indicated preterm birth such as idiopathic preterm labor, PPROM, and medical or care-related indications and complications having different etiologies but similar manifestations; these may include severe preeclampsia, placental abruption, and chorioamnionitis [19].

In our current study we documented pregnancy outcomes of pregnant patients with FMF. We showed that their perinatal results were comparable with healthy pregnant women. In this cohort, all participants with FMF continued their colchicine treatment during pregnancy from first trimester safely, and no significant differences were noted regarding congenital malformations.

The strengths of our study are the homogeneity of the characteristics of the women in the study groups and its prospective design. All of the participants were examined for infection and body temperatures were measured before obtaining blood samples. Patients with any signs and symptoms of active infection (pain, fever, or vaginal discharge) were excluded from the study. Moreover, in the present study, since the BMI, the maternal age, and the ethnicity were comparable between the groups, possible confounding effects were also eliminated.

In conclusion, the main findings of our study were that serum hs-CRP levels were still higher and MPV values were lower in pregnant patients with FMF who had already been put on colchicine treatment during the asymptomatic period. On the basis of this observation, it is hypothesized that MPV not only indicates platelet function and activation but also is inversely associated with systemic inflammation. Furthermore, perinatal outcome of patients with FMF was comparable to the patients without FMF.

Acknowledgements: The authors would like to thank Dr. Ozgur Kirbas for his secretarial help.

Competing interests

The authors declare that they have no competing interests.

References

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Introduction

Corneal opacity is a leading cause of monocular blindness worldwide. The definitive treatment of visually-impairing corneal opacity is penetrating allogenic keratoplasty using donor corneal tissue. Although corneal scar and keratitis are the most frequent indications for keratoplasty in developing countries, corneal edema and keratoconus constitute the majority of patients undergoing penetrating keratoplasty in developed countries. The reported success rate for penetrating corneal grafts is 73% at 5 years, and 62% at 10 years [1]. However, endothelial rejection rates are 15-20% in adults and 10-50% in pediatric grafts [2,3]. Rejection rates are higher in pediatric corneal transplantation because of the more active immune systems of younger patients [4]. In addition to rejection, late corneal failure is anticipated due to the continuing loss of donor corneal endothelial cells with time [5]. More importantly, the accessibility to corneal tissue for corneal grafting is a major limiting factor. Because of the increasing gap between demand and supply of donor corneal tissue, alternative techniques have been devised.

One of them is rotational autokeratoplasty, which is indicated for patients with a limited corneal opacity involving the visual axis. This procedure involves a rotation of the patient’s own cornea to move opacity out of the visual axis and to replace it with clear cornea [4,6-9].

Several authors have suggested the use of different graft shapes for ipsilateral autokeratoplasty, such as a triangle or a figure eight [9,10]. However, none has replaced the standard circular graft with an eccentric center [11-15].

Like any other surgical technique, appropriate patient selection is required for successful rotational autokeratoplasty. Usually rotational autokeratoplasty is chosen for nonprogressive corneal scars following blunt and penetrating corneal trauma, postinfectious keratitis scar, chemical injuries, and idiopathic or postherpetic lipid keratopathy [6,8,9,16,17]. These patients are at high risk of allograft corneal rejection if subjected to a conventional keratoplasty. Other than the usual indications, Cunha et al. described ipsilateral penetrating autokeratoplasty associated with a crescent-shape resection of 0.5 mm of the inferior cornea as an alternative method to corneal transplantation for keratoconus. They reported reduction of visual acuity with increased astigmatism during the follow-up period [18].

An important consideration during selection of cases for rotational autokeratoplasty is the dimensions of the corneal scar. A four to five mm of clear peripheral cornea is required to obtain at least 3 mm of central clear cornea, free of suture track scars.

Surgical Technique

The surgical technique performed is identical to that of conventional penetrating keratoplasty, with the exception that the host cornea is eccentrically cut and then rotated before suturing. Because of the more rapid loosening of sutures that occurs when they are placed into the anterior sclera, interrupted sutures are recommended for rotational autokeratoplasty.

Several authors have described methods for determining the size and location of the trephination. McDonnell et al. [9] recommended the following guidelines:

“1. Use the maximum area of available clear cornea (this usually meant making the peripheral edge of the graft very near the limbus).

2. Try to ensure that the opacity to be rotated is as near the edge of the graft as possible; this allows maximum movement of the opacity by the rotation and its replacement with the maximum area of the clear cornea.

3. Make the central edge of the graft at least 3 mm away from the visual axis. This ensures clear cornea at the visual axis and minimizes the affect [sic] of the suture.

4. If possible, rotate the opacity under the upper lid.”

In guidelines formalised by Roa and Lam [14], the center of the cornea is marked and a point 2.5 mm away from the center is marked in the opacity. A third mark is made 2.0 mm away from the central mark in line with the second mark, and a fourth mark is made 3.5 mm away from the third. The distance between marks 2 and 4 is taken as the trephine size to be used [14] (Figure 1).

The mathematical formulas for determining the size of the donor and host trephination have been described by several authors. The two most useful are described by Bourne and Brubaker [19] and Jonas et al. [7]. In Bourne and Brubaker’s method [19], two measurements were taken. First, the diameter of the largest circle of the clear cornea was measured. Second, the shortest distance from the edge of this circle to the geometric center of the cornea was assessed (this was considered positive if the opacity involved the center of the cornea and negative if the opacity was within the largest area of the clear cornea). The required trephine size was obtained with the following equation: 1.5 multiplied by the diameter of the largest clear circle added to the shortest distance from the circle to the corneal center [19]. The other formula, by Jonas et al. [7], utilises a trephine size of 0.75 of the overall corneal diameter, when the scar lies at the geometric center of the cornea, and adjusts this according to extent of the scar. Both the Jonas et al. [7] and Bourne and Brubaker formulas [19] give similar results, with the Jonas et al. [7] formula resulting in a slightly larger trephine size.

Another approach to postoperative simulation of rotational autokeratoplasty uses digital imaging. Agarwal et al. [15] have described the use of digital image manipulation software (Adobe Photoshop, version 5.0) to plan the size, location, and rotation of the graft. Using the drawing tool, a circle approximating the pupil was drawn on a new transparent layer created on the original image of the eye. Subsequently, a circle was drawn on the original photograph of the cornea to simulate corneal trephination. The corneal area within this circle was rotated on the image to simulate rotational autokeratoplasty. This step was repeated using varying sizes and positions of the larger circle, which simulated the corneal trephine, to include the maximum area of the clear cornea within the pupillary axis [15].

Outcomes

Several case series have been reported, as presented in Table 1.

In previously published studies of autokeratoplasty, graft survival was noted to be ≥ 90%. In a study by Murty et al. [6], only 3 of 22 grafts failed, two because of prolonged operative time and one because of uncontrolled glaucoma. Ramappa et al. [4] reported that the success rate was 81.25% over a mean follow-up of 29.43 months in pediatric patients. Bertelmann et al. [18] reported only one failure out of seven cases, which they attributed to a triple procedure and preoperative poor endothelial cell count (1200 cells/mm2). Continued endothelial loss is the major cause of graft failure following allograft corneal transplantation. Although long-term results are unknown, Bertelmann et al. [20] showed that mean endothelial cell loss at 1 year was 15% in rotational autografts compared with 40% in homografts.

The published case series in the literature have reported significant number of patients achieving good visual outcomes. In a report by McDonnell and Falcon [9], 2 patients did not have any astigmatic correction and four other patients had correction ranging from 1.25 to 4 D cyl. Murty et al. [6] reported 1 to 2.5 D cyl in 58.8% of patients, 3 to 5.5 D cyl in 23.5%, and 6 to 9 D cyl in 29.4%. Only Jonas et al. [7] compared visual outcomes after rotational autokeratoplasty with those of a nonrandomized control group of penetrating allografts, and found significantly lower postoperative visual acuity and higher corneal astigmatism in patients having rotational autokeratoplasty. The eccentric trephination, disparity of corneal thickness between the peripheral clear cornea and the central scarred cornea into which it is sutured, and the proximity of one edge of the trephination to the center of the cornea are potential reasons for increased astigmatism after rotational autokeratoplasty [7].

The most common postoperative complication reported after rotational autokeratoplasty was wound leak [6]. This was probably because of the difficulties in tissue apposition while suturing due to differences in the thickness of the central and peripheral cornea as well as scarred versus normal tissue. Also, the cosmetic outcome of autokeratoplasty is inferior to that of conventional penetrating keratoplasty. The corneal opacity is visible postoperatively, although it seems smaller because it is bisected during trephination.

Although rotational autokeratoplasty does not provide as high a level of best-corrected visual acuity as penetrating keratoplasty due to higher astigmatism, there are several advantages that outweigh these disadvantages in many patients whose risk of allograft rejection is higher than normal, such as pediatric patients and those with vascularised cornea:

1. This technique does not require a donor cornea and there is no risk of transmission of infection such as human immunodeficiency virus or hepatitis.

2. Most importantly, this technique obviates the lifelong risk of allograft rejection. This can be a very important factor in some patients, such as those with traumatised eyes with extensive corneal vascularisation, in children or young adults, and in those where follow-up is difficult.

3. Another advantage is reduced healing time, which allows early suture removal and reduction in the dose and duration of corticosteroid use postoperatively, thus avoiding steroid-induced complications such as cataract and glaucoma.

Conclusions

Ipsilateral rotational autokeratoplasty can be a viable alternative to conventional penetrating keratoplasty in some patients whose risk of allograft rejection is higher than normal. It avoids the risk of allograft rejection or long-term use of corticosteroids and obviates the waiting period for high-quality donor cornea tissues. Careful selection of patients can yield encouraging results with the use of this alternative technique.

Competing interests

The authors declare that they have no competing interests.

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