Insights into familial Mediterranean fever: Chronic disease correlations with arthralgia and current health status of patients with familial Mediterranean fever in Jordan

Introduction

Familial Mediterranean fever (FMF) is one of the world’s most common inherited auto-inflammatory diseases. Even though it mainly affects populations from the East Mediterranean region, FMF cases are reported worldwide. According to past research, the prevalence of FMF in Jordan has been estimated to be 0.04%.^[1] FMF is caused by functional mutations in the MEFV gene, which codes a protein called pyrin that mainly regulates the intrinsic immune system.^[2] FMF symptoms are described by self-limiting events of fever associated with arthritis, serositis, and dermal manifestations, lasting 12–72 h with a variable recurrence rate.^[3]

Recent systematic studies have defined several inflammatory conditions in FMF, like arthritis, rash, peritonitis, pleuritis, and typically fever.^{[4, 5, 6]} FMF unveils a complex interplay with chronic diseases such as hypertension, shedding light on the multifaceted health challenges faced by patients. Recent studies have underscored a significant association between FMF and hypertension, implicating potential synergistic effects on symptom severity.^[7] Since diagnosis of FMF is challenging in clinical practice, several arrays of classification and diagnostic standards for FMF have been used. The first criteria was set for adults by the specialists in Hashomer Medical Centre in 1997,^[8,9] followed be criteria’s implemented for children diagnosis purposes in 2009.^[10] Colchicine has been the primary treatment for FMF since 1972.^[11] Colchicine is correlated to pyrin and acts by changing the organization of actin cytoskeleton through binding to tubulin monomers and preventing polymer formation.^[12]

Based on the current research, it is highly recommended to assess genetic analysis of the MEFV gene in order to clearly diagnose a patient as having FMF, however diagnosis based on clinical presentation is still widely implemented in Jordan.^[13] Few studies investigated the status of FMF in Jordan, with their main focus was on children with FMF and finding FMF mutation types in Jordan.^{[14, 15, 16]}

Status of the general health of FMF patients at different age groups was not investigated recently in Jordan, neither any association of the disease status with several important factors like the degree of kinship between parents and spouses, treatment compliance, patient demographics, and pregnancy status. Our study aims to update the current health status of FMF patients in Jordan from patient point of view, to find any present association between chronic diseases and severity of symptoms, and to assess if there is a need for FMF premarital testing in Jordan.

Methods

Results

A total of 67 patients diagnosed with FMF accepted to participate in the study and successfully completed the survey. The majority of participants were Jordanian (n = 55, 82.1%), between 18–31 years old (n = 22, 32.8%), born in Jordan (n = 51, 76.1%) and resident in the central region (n = 30, 44.8%) or the northern part of Jordan (n = 34, 50.7%). Of all the participants 82% were identified as FMF patients while 18% were identified as FMF gene carriers. Detailed demographic data are shown in Table 2.

Out of the study subjects 7.5% of the married FMF patients were first degree relatives; cousins from mother side, father side or both, while 7.5% were second degree relatives and 73.1% were not. However according to our results first degree related parents diagnosed with FMF revealed the probability of 60% of transmitting FMF to their offspring’s. In comparison with non-related parents diagnosed with FMF only 10% probability exist (Chi-square test; 2, N = 67, χ² = 13.58, P = 0.001,). With regard to the kinship between FMF patient parents, 25.4% (n = 17) were first degree relatives, while 31.3% (n = 21) were second degree relatives. Therefore, 82.1% (n = 45) of the study patients believe that is important to perform pre-marital testing for FMF mutations.

Regarding FMF diagnosis, blood genetic testing is considered the first practice (n = 39, 58.2%). However, 23.9% of the patients were still diagnosed based on symptoms, 3% based on appendix removal then blood testing, 6% based on suspected appendicitis while the rest were diagnosed by chance. Most of the patients start to suffer from FMF symptoms between the age 5–12 years (n = 24, 35.8%) or 13–20 years (n = 21, 31.3%). On the other hand, a minority of the participants experienced their first symptoms before 5 years or after 21 years (9% and 13.5% respectively).

It is noteworthy to mention that most of the patients suffer from episodes of abdominal pain, fever, arthralgia and myalgia during acute disease attack. Moreover, most patients suffer from insomnia and general fatigue post attack. Table 3 shows the relative frequencies and percentages to such symptoms. Among the patients, only 75.4% feel well post FMF attack.

According to the study results, the participants suffer from other chronic comorbidities like diabetes, hypertension, asthma, gastrointestinal tract diseases, autoimmune diseases, cardiovascular diseases, or urinary tract diseases. As shown from Figure 1, hypertension was the most common incident among study participants. Using Chi-square test, there was an association between hypertension among FMF patients and the occurrences of myalgia χ² [(1, N = 49) = 7.29, P ˂ 0.05, Chi-square test] and Arthralgia χ² [(1, N = 49) = 4.94, P ˂ 0.05, Chi-square test]. On the other side, there were no other associations between the presence of other comorbidities and the severity and the occurrence of symptoms during or post disease attacks (P > 0.05, Chi-square test).

Figure 1

FMF patients with chronic comorbidities (N =24 out of 67). GIT, gastrointestinal tract.

Regarding clinical practice colchicine is the primary treatment modality used for FMF (89.6%). Other drugs are also used to lesser extent as corticosteroids (1.5%), non-steroidal anti-inflammatory agent like diclofenac sodium (1.5%). According to this study’s results, biological treatments were never mentioned to be used. Pertaining to treatment compliance, 90.3% of the study patients state that they are adherent to the treatment. Among the study subjects, only 88.5% take their medications regularly while 11.5% taking it during attack only.

Discussion

FMF is one of the most monogenic auto-inflammatory diseases, inherited autosomal recessively. However, based on previous research heterozygote mutation and patients with only one mutation would get FMF disease expression.^[23]

Based on our results, first degree related FMF parents would have 60% chance to get their children having FMF. Previous studies have supported this outcome, as a substantial body of research has indicated a higher incidence of MEFV gene mutation in siblings of first-degree relatives of FMF patients.^[24,25] Lachmann and coworkers studied FMF in a group of FMF patients, where 84% of them had at least two mutations and 12% had single mutation. According to their study group, 92% of first-degree relatives (parents or siblings) of these patients had mutation in MEFV gene.^[24]

Patients diagnosed with FMF in Jordan were desperately upset from the premarital screening. Therefore, 82.1% of the study patients believe that is important to perform pre-marital testing for FMF mutations. This remarkable result would in part reflect the actual status of premarital screening in Jordan since the national premarital screening program in Jordan includes primarily thalassemia screening. Besides, this screening is performed at the Ministry of Health without paying consideration to any updates or effort to include other genetic mutations. Since the Arabic culture traditionally encourages first degree relatives’ marriage, we believe that our study would raise attention in the region to start including such important modifications. It is of high importance to initiate a nationwide initiative to explore the importance of premarital tests, along with the high risks associated with getting fake results. Unfortunately, good percentage of Jordanians tries their best to escape from such test although it is free and noninvasive one. This could be attributed to cultural beliefs or lack of awareness, rather than any other alternative reason.

After the Syrian crisis in 2011, the influx of Syrian refugees has placed significant pressures on the availability of existing services within hosting countries, specifically on health and education.^[26] Consequently, Syrian refugee participated in the increment of FMF cases in Jordan.^[27] Moreover, as the refugee camps are closed and performing scientific studies need complicated permission, studying such communities remains of high priority. It is noteworthy to mention that consanguineous marriage among such closed communities is very high. This is due to cultural beliefs, economic issues, and lack of awareness. Considering these facts and as these refugees are integrated in Jordanian community, studying the prevalence of FMF among them become of high importance.

FMF diagnosis according to our study was primarily performed through genetic blood testing, with some exceptions at which patients’ diagnosis was mainly based on symptoms. While other patients were suspected to have appendicitis or performed appendectomy then diagnosed with FMF. This misdiagnosis of FMF still present a challenge worldwide as past research reported such cases were patient were misdiagnosed with appendicitis or rheumatic fever before FMF with the most common misdiagnoses was appendicitis.^{[28, 29, 30]} Moreover, as found from our results surgical misdiagnosis of FMF patients is still present. This result is also had been investigated in many studies that concluded that acute abdominal pain suffered by FMF patients may lead to an unnecessary laparotomy before FMF diagnosis.^[31]

Common clinical features of FMF indicate that recurrent episodes of abdominal pain and fever still the main distress suffered by FMF patients.^[14,32] Those two symptoms; fever and abdominal pain are also mostly suffered by the study participants beside arthralgia and myalgia just before and during the disease attack.

On the other hand, most of the study patients suffered from insomnia and general fatigue just after the disease attack. As they state that disease attacks are most of the time connected to a state of irritability, insomnia and fatigue. This result can be explained according to the published literature in two ways; one in part is related to the used treatment during the disease attack which is colchicine as one of the study connected colchicine therapy to major depressive state affect the patients upon medication administration.^[33] The other explanation could be related to the disease state is self as FMF attacks may be triggered due to change in the circadian rhythm or the attack itself my lead to emotional distress and sleep disturbances.^[34] Other published literature found a state of increased histamine levels in FMF patients that may lead to a state of insomnia.^[35] Our results need further investigation since few studies are published with regard to this issue.

Many systems are affected by FMF, including the renal, mus-culoskeletal, and gastrointestinal systems. Moreover cardiovascular involvements are still reported, it is essential to diagnose those complications as early as possible as some of them can lead to an increase in morbidities and/ or mortality.^[36] As shown by our study results, the participants suffer from chronic morbidities like the previously mentioned. Hypertension incidence was the highest among study participants compared to other diseases, and it was associated with an increase in the severity of arthralgia and myalgia. The association of FMF and cardiovascular disease was investigated in past research and attributed to the subclinical atherosclerosis and Deposition of amyloid.^[37] Research by Yalçinkaya et al. (2019) demonstrated a compelling link between hypertension and heightened occurrences of myalgia and arthralgia among FMF patients in Jordan. This correlation not only underscores the intricate pathophysiological mechanisms underlying FMF but also highlights the critical importance of comprehensive management strategies tailored to address both FMF-related symptoms and co-existing chronic conditions. As such, elucidating these associations not only enhances our understanding of FMF pathogenesis but also paves the way for more targeted and effective therapeutic interventions aimed at improving patient outcomes.^[38]

Colchicine is the primary treatment of FMF as found in the current literature and clinical practice all over the world.^[39] This practice is still adopted in Jordan as we can found from our results that our patients were mainly on colchicine treatment either on a regular base or during FMF attacks.

Conclusion

In conclusion, our study sheds light on the interplay between FMF and chronic diseases, particularly highlighting the association with hypertension and its impact on symptom severity among FMF patients in Jordan. Our findings assert the importance of premarital tests and shed light on the importance of incorporating FMF test as part of premarital testing. The issue of misdiagnosis remains a major challenge in Jordanian clinical practice. This emphasizes the urgency of instituting advanced training programs for health care providers.