Proposed mechanism of the inflammatory attacks in familial Mediterranean fever

Peritoneal and synovial fluids of patients with familial Mediterranean fever lack a protein that inhibits neutrophil chemotaxis by antagonizing the complement-derived inflammatory mediator C5a. The C5a inhibitor activity was studied with the use of a C5a binding assay where peritoneal fluids were tested for their ability to inhibit recombinant C5a binding to dibutyryl cyclic adenosine monophosphate-induced U937 cells. In contrast to normal peritoneal fluids, those from patients with familial Mediterranean fever contained less than 1% C5a inhibitor activity. Gel filtration and ion exchange chromatography of peritoneal fluids from those patients did not yield any fraction that inhibited C5a binding. We suggest that the serosal tissue of patients with familial Mediterranean fever is devoid of C5a inhibitor activity and that this deficiency may explain in part the local inflammatory episodes characteristic of this disease.     

The relations between attacks and menstrual periods and pregnancies of familial Mediterranean fever patients

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by short lived, febrile serosal inflammatory attacks. Although majority of patients have random pattern of attacks, some reports described precipitating factors. There are also contradictory reports relating FMF attacks with menstruation and the natural course of their pregnancies. Seventy-two female patients with FMF with a mean age of 34.9±12.4 were interviewed. A standardized questionnaire was used inquiring any associations of FMF attacks of the patients with their menstruations and pregnancies. Thirty-eight patients (53%) reported that their attacks frequently coincided with their menstrual cycles and 17 patients noticed pleuritic chest pain in addition to their abdominal attacks. One patient experienced only febrile pleural attacks during her menstrual cycles. Unlike dysmenorrhoea, none of these patients’ attacks responded to non-steroidal anti-inflammatory drugs. All of the patients could correctly differentiate their FMF attacks from dysmenorrhoea. Forty patients could give detailed information about the frequency and severity of their FMF attacks during 73 pregnancies: 25 patients (62.5%) experienced complete symptomatic remissions; the attacks were aggravated (7 patients), ameliorated (6 patients) or did not change (2 patients) in the rest of the pregnancies. Four patients continued to use colchicine during their pregnancies and delivered healthy babies. One patient gave birth to a child with Down’s syndrome although she was not on colchicine therapy. Although FMF attacks and discomforts of menstrual cycles do overlap frequently, patients can easily differentiated them. Patients can be reasonably assured that the period of pregnancy will be comfortable but abstaining from colchicine should not be recommended. Gynecologists must be aware of FMF in the differential diagnosis of dysmenorrhoea or endometriosis.     

Crohn disease in patients with familial Mediterranean fever

Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 +/- 10.0 yr versus 26.2 +/- 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.     

Fatigue in pediatric patients with familial Mediterranean fever

Abstract

Objectives: Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited attacks of fever with serositis involving the peritoneum, pleura and joints. Fatigue is a common problem in many pediatric rheumatic diseases; however, has not been evaluated systematically in FMF patients. Accordingly, the aim of this study was to evaluate fatigue and its possible allied factors in patients with FMF.

Methods: Patients with FMF, aged between 10 and 21 years, were assessed by completed validated fatigue questionnaire (Checklist Individual Strength-20). As a control group, patients with chronic rheumatic diseases and healthy children without any chronic disease were included.

Results: The study group comprised 111 patients with FMF, 54 with other chronic rheumatic diseases and 79 healthy subjects. While the CIS-20 total score and subscale scores (including subjective experience of fatigue) were similar between patients with FMF and those with other chronic rheumatic diseases (p?>?.05); both groups had significantly higher scores when compared with healthy subjects (p?<?.05). FMF patients with musculoskeletal complaints had significantly higher scores of subjective experiences of fatigue when compared to those without those complaints.

Conclusions: Fatigue is a common but unrecognized complaint in patients with FMF. Familial Mediterranean fever seems to be a chronic disease with inter attack ongoing complaints.     

Renal transplantation in patients with familial Mediterranean fever

Amyloidosis is the most common and devastating complication of familial Mediterranean fever (FMF). Renal transplantation is the choice of treatment of in most end-stage renal disease (ESRD). We report our experience on the outcomes in eight patients who underwent renal transplantation for ESRD due to FMF secondary to amyloidosis, and we provide a discussion on the current evidence on this topic of study. The clinical charts of eight renal transplant patients (seven male, one female) who underwent ESRD due to FMF-related amyloidosis were investigated. Five patients underwent living-donor renal transplantation and three patients underwent deceased-donor renal transplant. The mean follow-up period was 35 months (range 3-72). All patients were on triple immunosuppressive treatment and received colchicine. All allografts are currently functioning well with a mean serum creatinine level of 1.4 (range 0.7-2.6) mg/dL. Posttransplantation complications included acute rejection (n = 4), chronic rejection (n = 1), severe gastroenteritis (n = 2), and erythrocytosis (n = 5). None of the patients had proteinuria. During follow-up, we did not observe clinically severe FMF attack, septicemia, rhabdomylosis, symptoms related to vasculitis, and clinical neuropathy. The clinical outcome of the patients in this cohort was similar to that of other renal transplant patients with ESRD due to other causes. This study shows favorable prognosis of eight ESRD patients due to amyloidosis caused by FMF after renal transplantation. Renal transplantation is a safe procedure for ESRD patients having amyloidosis due to FMF. Regular use of colchicine after transplantation should be mentioned.     

Bone mineral density in patients with familial Mediterranean fever

This study was carried out to determine lumbar and femoral bone mineral density (BMD) in patients with familial Mediterranean fever (FMF), an autosomal-recessive disease characterized by recurrent episodes of peritonitis, pleuritis, and arthritis, which are usually associated with fever. In patients with FMF and control subjects, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured. BMD was determined at the lumbar spine (L1–4) and the femoral regions (neck and total) using dual energy X-ray absorptiometry. Twenty-eight FMF patients and 30 control subjects without a history of inflammatory disease participated in our study. The demographic variables, such as age, sex and body mass index were similar between patients and controls (P > 0.05). We found statistically significant difference in ESR and CRP between FMF patients and controls (P < 0.01, P < 0.05 respectively). There was statistically significant difference in lumbar spine, femoral neck, and total femur BMD between FMF patients and control groups (P < 0.001, P < 0.01, P < 0.01 respectively).Our study indicates that lumbar spine and femoral neck and total femur BMD in patients with FMF may be lower than in healthy subjects.     

Adrenal axis functions in patients with familial Mediterranean fever

Objective: Familial Mediterranean fever (FMF) is a hereditary disease characterized by recurrent attacks of fever with peritonitis, arthritis, pleuritis or erysipelas-like rash. It is unclear what effects of FMF itself on endocrine system and hormones are. None of the FMF patients without amyloidosis have been reported to have any endocrine disorders, except those who developed colchicine-induced diabetes insipidus. There is a large body of evidence to show that cytokines (IL-1, IL-6 and TNF-α) activate the hypothalamic-pituitary-adrenal (HPA) axis. We have designated this study to investigate the HPA axis in FMF patients without amyloidosis. Methods: Twenty-one patients with FMF were included. ACTH stimulation test was performed on the healthy subjects and during attack period in the patients. In the patient group, same test was repeated during remission period. Results: Peak cortisol levels were significantly higher in the attack period than those in the remission period of patients (p<0.05). Conclusion: The cytokines play a role on the activation of the HPA axis; we thought the axis would be affected in this disease. The response of cortisol to 250 μg ACTH was significant in attack period when compared with remission period. This result reveals that HPA axis is more activated in an FMF attack. Previous studies suggest that the adrenal hormones increase in acute inflammatory events, and eventually, the changes on these hormones are related to TNF and IL-6 levels. During the FMF attack, HPA axis may be stimulated by cytokines. It seems that HPA axis is regulated normally in FMF patients.An erratum to this article can be found at     

Comparing D-dimer status in children with familial Mediterranean fever during and in between acute attacks

Aim of the work

To compare the D-dimer status in children with familial Mediterranean fever (FMF) during, and in between acute attacks.

Continuity of cytokine activation in patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is a recessively inherited inflammatory disorder, characterized by recurrent attacks of fever and polyserositis. It has been considered that miscellaneous cytokines take part in the pathogenesis of the disease. The aim of this study was to investigate serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), and interleukin-10 (IL-10) in patients with FMF. The study included 42 patients with FMF (3 females, 39 males, mean age: 24.43 years) and 20 healthy volunteers as the control group (18 males, 2 females, mean age: 23.2 years). The patients were chosen according to Eliakim criteria. After recording their history and performing an examination, leukocyte counts, erythrocyte sedimentation rates (ESR), C-reactive protein (CRP), fibrinogen, sIL-2R, IL-6, and IL-10 levels were measured before and during attacks. A significant increase was found in leukocyte (p<0.001), ESR (p<0.001), CRP (p<0.001), and fibrinogen (p<0.001) levels of the patient group in the attack period compared to those in the quiescent state. sIL-2R (p=0.019) and IL-6 (p<0.001) levels showed significant increases during attacks compared to the levels before an attack. There was no significant difference between IL-10 levels. The levels of the three cytokines were significantly high both before and during the attacks compared to the control group. As a result, the elevation of sIL-2R and IL-6 levels both before and during the attacks compared to control group suggests the existence of continuous cytokine activation in the patients. No significant increase in the IL-10 levels in spite of the significant rise of sIL-2R and IL-6 during attacks supports the notion of inflammation and also reveals that compensation by anti-inflammatory IL-10 does not seem to occur.     

Periodic fever compatible with familial Mediterranean fever.

A 55-year-old male presented with a recurrent fever of over 38 degrees C, occurring at irregular intervals 1-6 times a month with chest, back or abdominal pain. After admission to our hospital, we found the following characteristics: 1) the febrile attacks were accompanied by obvious inflammatory findings and pleuritis or peritonitis; 2) the patient's elder sister had a similar periodic fever; and 3) there were no apparent causative factors responsible for his symptoms. Therefore, we diagnosed this as a case compatible with familial Mediterranean fever. The febrile attacks have been completely suppressed by daily colchicine. This is the seventh case of familial Mediterranean fever reported in Japan.