Background

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disorder that is particularly frequent in Turkish, Armenian, Jewish, and Arabic communities [1, 2]. It is the most common member of the family of monogenic autoinflammatory disorders. It is due to mutations in the Mediterranean fever (MEFV) gene, which encodes pyrin, a protein that plays a role in the regulation of both inflammation and apoptosis [3,4,5].

Familial Mediterranean fever is characterized by relapsing and remitting episodes of one to three days of fever, sterile serositis, arthritis, and an erysipeloid erythematous rash with elevations of serum inflammatory markers [6, 7]. Serositis most commonly presents as sterile peritonitis, although, pleuritis and pericarditis may also be present [8,9,10].

The arthritis of FMF is usually in the form of acute attacks of pain and swelling, most frequently affecting large joints of the lower extremities, although the shoulder, sternoclavicular or temporomandibular joints may also be involved. These attacks usually disappear within 2–3 days, and despite recurrent episodes of arthritis, there are no permanent sequelae of the affected joints. However, in about 5% of the patients, protracted arthritis develops, almost involving the hips or knees. Although complete recovery is the rule, disabling joint damage can occur and even may lead to joint replacement [11,12,13,14,15,16]. Myalgia is also a common manifestation of FMF and occurs in about 20% of patients. Protracted febrile myalgia syndrome is a unique syndrome, that has been described in patients with FMF, characterized by severe, disabling muscle pain and tenderness lasting several weeks, which responds only to corticosteroid therapy [17, 18].

Although FMF is a polyserositis disease, there is also central nervous system (CNS) involvement and many associated neurological manifestations. The pathogenesis of CNS involvement is unclear and is a subject of debate. Demyelinating lesions, septic meningitis, and pseudotumor cerebri have been reported in FMF patients [19, 20].

The diversity of the clinical manifestations of FMF can often delay the diagnosis. To date, the identification of the FMF gene and its various mutations provides the application of an accessible, non-invasive, and sensitive molecular genetic test for an accurate diagnosis of this fascinating disease [21]. The location of the MEFV gene has been mapped on the short arm of chromosome 16 at position 13.3 (16p13.3) with about 280 mutations have been described for FMF, nine of them(E167D, T267I, M694V, V726A, M680I, M694I, R761H, A744S, I692del) are clearly pathogenic while the most frequent MEFV gene mutations are M694V, V726A, E148Q, M680I, and M694I respectively [22, 23]

The aim of the current work is to describe the various musculoskeletal and neurological manifestations in a cohort of Egyptian FMF patients and to evaluate their relation to the different MEFV gene mutations Tables 1, 2, 3, 4, 5, 6 and 7.

Table 1 Distribution of the studied cases according to different demographic and clinical parameters (n=145)
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Table 2 Distribution of the studied cases according to types of MEFV gene mutation (n=145)
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Table 3 Comparison between the different types of MEFV gene mutation according to the presenting manifestation
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Table 4 Comparison between the different types of MEFV gene mutation according to the age of onset and serum amyloid A
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Table 5 Comparison between the different types of MEFV gene mutation according to Colchicine dose and ESR level
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Table 6 Comparison between the different types of MEFV gene mutation according to different Musculoskeletal manifestations
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Table 7 Comparison between the different types of MEFV gene mutation according neurological manifestations
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Methods

In this retrospective study, the medical records of all FMF patients (diagnosed according to Tel-Hashomer criteria [24]) under follow-up at the outpatient clinics of our University hospitals through the period from June 2018 to July 2021, were included. 145 patients were involved. We described the musculoskeletal and neurological features of these patients, in whom genetic screening revealed homozygosity for the MEFV gene. MEFV gene mutation was detected using several multiplex Real-Time PCR reactions. Any patient with associated rheumatologic or neurologic diseases as juvenile idiopathic arthritis, rheumatoid arthritis, spondarthropathies, demyelinating disease, or hereditary neuropathy were excluded. We also reported the correlations between the musculoskeletal manifestations, neurological manifestations, and other features of the disease with the type of MEFV gene mutation.

Data collection

The following data were retrieved from the records of eligible patients: demographics characteristics, disease presentation, different musculoskeletal and neurological manifestations, ESR and serum amyloid A level during the last follow-up visit of the patients, colchicine dose at disease onset and currently and the type of MEFV gene mutation.

Statistical Analysis

Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). The Kolmogorov- Smirnov was used to verify the normality of distribution of variables, Comparisons between groups for categorical variables were assessed using the Chi-square test (Monte Carlo). Mann Whitney test was used to compare between two groups for not normally distributed quantitative variables. The significance of the obtained results was judged at the 5% level

Results

This study involved 145 FMF patients, of them 62.1% were females and 31.7% were in the pediatric age. The presenting manifestation in 71.9% of these patients was abdominal pain followed by musculoskeletal manifestations in 35.2% of them in the form of arthralgia, myalgia, and arthritis, to be followed by fever in 30.4%.

Regarding the musculoskeletal manifestations, 38.6 % of the involved patients had arthritis during the period of follow-up. The most commonly affected joints were the knee and ankle, the small joints of the feet, and the hands respectively. Monoarthritis was the most frequent pattern of arthritis, being present in 26.9% (39 patients) of the studied patients. Arthralgia was the most prominent musculoskeletal manifestation, presenting in 96.6% of the studied patients with also the knee as the most frequent joint, followed by the ankle, feet, and lower back respectively. Myalgia was present in 19.3% of the studied patients (28 patients) involving the lower limb muscle (14 patients), upper limb muscles (10 patients), upper and lower limb muscles (3 patients) with one case of protracted febrile myalgia.

As regards the neurological manifestations, they were present in about 86.9 % of cases throughout the period of follow up. Vertigo was the most common manifestation as it was present in 22.8% (33 patients), paresthesia in 15.2%, while seizures was present in 12.4 % of the studied patients. Recurrent meningitis was reported in 9.7 % of the studied patients while pseudotumor cerebri presented in 9% . Less frequent symptoms were disorientation and cerebrovascular disorders as they were detected only in three, and one patient respectively.

As regards the MEFV genetic mutations, 5 major mutations were detected in most of the studied patients: M694V in 39 patients (26.9%), M680I in 37 patients (25.5%), E148Q in 25 patients (17.2%), V726A in 20 patients (13.8%), and M694I in 14 patients (9.7%). These genetic mutations account for 93.1% (135 patients) of the involved patients.

When a comparative study was done between these five major MEFV gene mutations according to the age of onset of the symptoms, different musculoskeletal and neurological manifestations, ESR, serum amyloid level, and dose of colchicine at the start of the disease and currently no statistically significant difference was found.

Discussion

This study involved 145 FMF patients (99 adult and 46 pediatric patients). The majority of the studied patients were female (62.1%) and this was in line with several studies from Egypt and Israel [11, 25]. Two other studies that were performed on Italian and Arabs showed a similar result [26, 27]. However Amal et al. [28] reported a higher male to female ratio in an Egyptian cohort. A larger sample size may be the cause of this discrepancy. The presenting manifestation in 71.9% of these patients was abdominal pain followed by musculoskeletal manifestations in 35.2% in the form of arthralgia, myalgia, and arthritis, to be followed by fever in 30.4% of patients. This is the same finding of other Egyptian studies [11, 29, 30], while Duşunsel et al. [31] reported that fever was the most common followed by abdominal pain in a cohort of Turkish FMF patients. It seems that the ethnicity of studied patients affects the clinical picture of the attacks.

In the current study, 80.7% of the studied patients used a colchicine dose of 1.5-3 mg daily. As abdominal pain was the commonest presenting symptom in our study, it was also the major cause of colchicine dose increase. In contrast, a study by Lidar et al. [14] reported that only 40% of patients used doses higher than 2mg. The different genotype of the studied patients is a major contributing factor for this conflict as the current study included only patients with homozygotic MEFV gene mutation which implies severe disease form.

The current study reported that the most common MEFV genetic mutation was M694V, M680I, E148Q, V726A, and M694I respectively and this is in agreement with several Arab and Turkish studies [30,31,32,33]. While a study by Brik et al. [12] showed a lower prevalence of M694V gene mutation in Israeli patients. Different ethnicity of studied patients might be the main cause.

We noted that a large percentage of our studied patients had raised serum Amyloid A, up to (87.9%) while Amal et al. [28] reported much lower serum Amyloid level (8.4 %). Delay in seeking medical advice, chronicity, severity of the disease, and different sample sizes are major factors for this discrepancy.

Regarding the musculoskeletal manifestations, 38.6 % of the involved patients had arthritis during the period of follow-up. This goes in accordance with two other Egyptian and Turkish studies [30, 34]. While Farag Y et al. [11] and other two Egyptian studies [29, 35] found lower frequency. On the other hand, a Turkish study [36] found a higher frequency of 57%. The period of follow-up, age of the patients, and chronicity of the disease can affect the frequency of arthritis. The most common joint affection was the knee and ankles, the small joints of the feet, and the hands respectively. This goes in accordance with Farag et al. [11] , Jargour and Dodaki [13] and Lidar M et al. [14] Monoarthritis was the most frequent pattern of arthritis, being present in 26.9% (39 patients) of the studied patients. This goes in accordance with many other studies [11, 14, 15, 36]. While Jarjour and Dodaki [13] found diarthritis as the most common pattern in a sample of Syrian FMF patients. No joint deformity was detected in these patients . Many other studies reported that Joint deformity and irreversible joint destruction has been very rarely noted in arthritis of FMF despite its recurrent nature [11, 12, 15].

Arthralgia was the most prominent musculoskeletal manifestation presenting in 96.6% of the studied patients with the knee as the most frequently affected joint, followed by the ankles, feet, and lower back. Other Israeli and Syrian studies reported arthralgia and arthritis as the most common symptoms of FMF patients [12, 13]. The long period of follow-up in the current work probably raised that frequency. Myalgia was present in 19.3% of the studied patients (28 patients) involving the lower limb muscle(14 patients) and Upper limb muscles(10 patients) with one case of protracted febrile myalgia. Many studies found myalgia to be as frequent as 20-40 % in FMF patients with the same distribution [17, 18]. While protracted febrile myalgia was reported to occur in 1:3% of FMF patients in different studies [17, 18, 37].

Regarding neurological manifestation, vertigo was the most common neurological symptom as it was detected in about 22.8% of the studied patients, followed by paresthesia and seizures. This was in accordance with a recent Iranian publication that detected vertigo in 27.7% of FMF patients and reported it as a common presentation in FMF [38].

In this study,15% of patients had paresthesia. Paresthesia was detected in 22% of the Iranian FMF cohort, as reported by Salehzadeh et al [39], whereas in Kalyoncu et al’s study of 18 Turkish patients with FMF who had neurologic symptoms, 11.1% had paresthesia [20]. Seizures were detected in 12.4%. Several researches on EEG abnormalities in FMF patients have been published, however, none of them provide a reliable explanation for the link between FMF and seizures [40,41,42,43]. Interestingly, the first link between seizure and FMF was in 1993 when seizures were detected in three Israel patients [44].

Headache was found only in five of our patients which is in contrast with other Iranian and Turkish studies [38, 45], while it was detected as a symptom of recurrent meningitis and pseudotumor cerebri and both are present in 9.7 % and 9% of our patients respectively. The presence of pseudotumor cerebri in conjunction with FMF has been described in the literature [46,47,48]. Severe headache and meningism may be observed during FMF attacks [48]. A severe type of headache in the form of FMF-like recurring meningitis has also been reported by Feld et al. [40]

When a comparative study was done between these five major MEFV gene mutations according to the age of onset of the symptoms, different musculoskeletal manifestations, ESR, serum amyloid level, and dose of colchicine at the start of the disease and currently, no statistically significant difference was found. This is not in accordance with many previous studies [49,50,51] that found arthritis and musculoskeletal manifestations related to and more frequent in M649V homozygote mutation but the ethnic and environmental factors must be predominant while dealing with FMF patients. Mohamed Elmalky et al. [52] in a recent study on Egyptian FMF patients, goes partially in accordance with our finding as regard amyloidosis and response to colchicine therapy as they didn’t find a correlation between the MEFV gene mutation type and these clinical parameters. However, in a mixed cohort of 220 Arab and Jewish patients with FMF, Gershoni-Baruch et al. [53] noted that homozygosity for M694V, V726A, and E148Q were associated with a severe course and the highest risk for amyloidosis. When a comparative study was done between the five major mutations and different neurological manifestations, no statistically significant difference was found. Unlike this finding, An Israeli study [40] mentioned that most patients with FMF, who experience severe FMF and present with neurologic manifestations had M694V gene mutation. Most of the previous studies compared neurological manifestations in MEFV gene-positive and negative patients, which is different from the current work, being concerned with homozygous MEFV gene mutation.

The limitation of the study was the relatively small number of patients included in the study but this was due to the exclusion of patients with heterozygotic gene mutation.

Conclusions

Musculoskeletal manifestation is the second most common presenting symptom in a cohort of Egyptian FMF patients after abdominal pain. Arthralgia is the most frequent musculoskeletal manifestation while monoarthritis of the knee or ankle joint is the most common pattern of arthritis in FMF patients. Vertigo, paresthesia, and seizures are the most frequent neurological manifestations. Musculoskeletal manifestations, neurological manifestations, serum amyloid level, and dose of colchicine are not related to the type of the genetic mutation in this cohort. Prospective clinical studies with different ethnic groups will help to better clarify the relationship between MEFV gene mutation and disease clinical features. Future research should focus on the musculoskeletal and neurological manifestations, with a larger number of FMF patients undergoing genetic testing and being followed for a longer period of time, including newer therapies.