Sustained, progressive, nonresolving abdominal pain: a previously undescribed clinical presentation of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a genetic disorder characterized by sporadic, acute attacks of fever and serosal inflammation. Typical manifestations are recurrent febrile episodes of acute instauration for brief duration (1 to 4 days) that is associated with severe pain due to serositis at one or more sites. Abdominal crisis occurs in 95% of the patients. Treatment with colchicine is highly effective as preventive treatment, but it is considered to be ineffective for the treatment of established acute attacks. As mentioned, untreated crisis resolves spontaneously in 1 to 4 days. Prolonged, nonresolving crisis of abdominal pain refractory to nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, with fever and elevation of acute phase reactants that resolves after the administration of colchicine, is a clinical presentation undescribed hitherto. The aim of this paper is to report a patient with this distinctively unusual clinical presentation of FMF.     

Familial Mediterranean fever with chronic ascites: a case report and a review of literature

Familial Mediterranean fever (FMF) is an autosomal recessive inflammatory disease especially seen in Turks, Sephardic Jews, Armenians, and Arabs. Peritoneal and pleural inflammation, arthritis, erysipelas-like erythema, and arthralgia are well-known features of FMF. A small amount of peritoneal fluid collection can be seen during peritoneal attacks in FMF patients, but chronic ascites is a rather rare complication. We herein report a female FMF patient who developed chronic ascites. She was compound heterozygote for M694V/M680I mutation of the MEFV gene. Aspiration of the ascites fluid revealed a small amount of erythrocytes and mesothelial cells. After dose adjustment of colchicine the amount of ascites decreased. In conclusion, FMF should be considered in the differential diagnosis of chronic ascites in populations where the disease is endemic.     

Abdominal and digestive system associations of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary epidosic febrile syndrome that is expressed by acute spells of fever, painful manifestations in the abdomen, chest and joints, and slow development of nephropathic amyloidosis. Despite the recent cloning of the FMF gene ( MEFV) and the identification of about 40 disease-related mutations, the diagnosis is still clinically dependent, and the pathogenesis and most of the clinical heterogeneity remain to be explained.
Because episodic abdominal pain affects 95% of FMF patients, most of them are seen by gastroenterologists and undergo complete or partial abdominal imaging before the diagnosis is made. Focusing on recent advances in FMF, this article reviews both common and infrequent manifestations that a gastroenterologist may encounter during workups of FMF patients. These include episodic abdominal pain, paralytic or mechanical ileus, constipation, diarrhea, ascites, malabsorption, bowel infarction, and bleeding, arising directly from FMF or secondary to FMF common associations such as amyloidosis, vasculitides, inflammatory bowel disease, irritable bowel syndrome, or colchicine side effects. This article will help the gastroenterologist to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF.     

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.     

A rare cause of massive ascites: familial Mediterranean fever

Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent fever and peritoneal and pleural inflammation. It is an inherited disorder commonly found in Armenians, Turks, Arabs, Balkans, and Jews originating from North African countries. A small amount of peritoneal fluid collection can be observed during peritoneal attacks in patients with Familial Mediterranean fever, but chronic ascites has been described rarely in these patients. A 42-year-old female patient was admitted to our clinic in June 2010 with fever, severe abdominal pain and abdominal distention that had continued for one month. There was no family history of periodic fevers or abdominal pain. We could not find any cause for ascites, including tuberculosis. A diagnosis of Familial Mediterranean fever was suspected based on the clinical findings and her family history. She was screened for mutations causing Familial Mediterranean fever, and when found to be homozygous for M694V, treatment with colchicine was initiated. After treatment, the amount of ascites decreased, and relief of symptoms was confirmed during a follow-up. In conclusion, because Familial Mediterranean fever is common in our country, it should be considered in the differential diagnosis of patients with ascites of unknown etiology in populations where hereditary inflammatory disease is endemic.     

Biologic therapy in familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common autoinflammatory hereditary disease characterized by self-limited attacks of fever and serositis. Although colchicine is the gold standard treatment for the attacks ～10% of cases of FMF are resistant or intolerant to effective doses of colchicine. In such cases, however, there are increasing numbers of case reports or clinical trials treated by biologic agents which directly target the proinflammatory cytokines. Anti-interleukin-1 (IL-1) treatment has proven beneficial in improving the inflammation in terms of clinical manifestations and laboratory findings in clinical trials. Furthermore, anti-tumor necrosis factor treatment has also revealed the efficacy and safety in patients with colchicine-resistant FMF. More recently, cases of successful treatment with IL-6 inhibitor, tocilizumab (TCZ), has been reported from Japan and Turkey. Of note, TCZ may be preferable in the treatment as well as the prevention of secondary amyloidosis of FMF patients since it significantly suppresses acute inflammatory response. In the present review, we summarize the literatures regarding the efficacy of biologic therapy in colchicine-resistant or -intolerant patients with FMF.     

Protracted Febrile Myalgia Syndrome with Henoch-Schönlein Purpura: an atypical presentation of Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is an hereditary autosomal recessive disease characterized by recurrent attacks of fever, arthritis and serositis: peritonitis, pleurisy and/or pericarditis. Its main complication is systemic AA amyloidosis. The authors present a case of a 8-years-old female child with african ancestry, who was admitted three times since 5 years-old with abdominal pain, fever and high acute phase reactants. At the first admission appendectomy was made and at the third hospital admission the clinical picture was accompanied by myalgia, purpuric lesions and non nephrotic proteinuria. A renal biopsy was performed and was compatible with Henoch-Sch?nlein nephritis. Serum Amyloid A protein had high levels - 92 mg/L (> 6.8) and a diagnosis of Familial Mediterranean Fever was confirmed by genetic test (homozygote for M694V in MEFV gene). She started colchicine and is doing well, without any further complaints. FMF must be considered in the differential diagnosis of recurrent attacks of fever and abdominal pain in children, even with an atypical presentation (p.e. Protracted Febrile Myalgia Syndrome). Genetic study allows the confirmation of the diagnosis and has prognostic implications.     

Regular abdominal pain and fever in each menstruation onset: an unusual menses-associated familial Mediterrenean fever attacks and a favor result on colchicine treatment

We present a 38-year-old woman suffering from regular abdominal pain and fever only in each menstruation onset for 7 years. The clinical symptoms, along with inflammatory findings during painful attacks, the beneficial effect of colchicine and genetic mutation (M694 V and M680I) supported the diagnosis of familial Mediterranean fever (FMF). A literature review indicated that FMF attacks occurring only during menstruation are rarely seen. This clinical picture may be confused with gynecological disorders especially in the people of Mediterranean origin.     

Diagnostic challenge in a Tunisian patient with Familial Mediterranean Fever,sacroiliitis and coxitis

Introduction

Familial Mediterranean Fever (FMF) is a hereditary auto inflammatory disease. The most common joint attack is an acute large joint monoarthritis most often affecting the knee or hip and lasting for several days. Rarely, a more protracted arthritis may occur.

Bloody Diarrhea as a Presentation Manifestation of Familial Mediterranean Fever in a Patient with Compound Heterozygote Mutations of the MEFV Gene

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by episodic fever and inflammatory polyserositis, which could lead to a variety of manifestations, including recurrent abdominal pain. Herein, a 12-year-old boy who has suffered from fever and bloody diarrhea since early childhood is described. All structural and underlying disorders leading to bleeding were excluded. Genetic studies indicated compound heterozygote mutations of M680I/R761H in the MEFV gene, which confirmed the diagnosis of FMF. Therefore, treatment with colchicine was started, which led to symptom relief. As gastrointestinal manifestations appear to be the main features of FMF, bloody diarrhea could also be considered an initial symptom of FMF.     

Familial Mediterranean fever--a not so unusual cause of abdominal pain

Familial Mediterranean fever is a hereditary syndrome characterised by recurrent episodes of fever and serositis, resulting in pain in the abdomen, chest, joints and muscles. It is primarily diagnosed in people of Jewish, Arabic, Turkish or Armenian ancestry and is caused by mutations in the gene encoding for pyrin. Abdominal FMF attacks resemble the clinical presentation of 'acute abdomen', with severe abdominal pain and rigidity, but in FMF symptoms always resolve spontaneously. It is important to distinguish these regular pain episodes from small bowel obstruction due to adhesions to prevent life-threatening bowel strangulation. In most cases, colchicine will prevent new painful attacks. This seminar also discusses other causes of abdominal pain in FMF patients.     

Accurate diagnosis of acute abdomen in FMF and acute appendicitis patients: how can we use procalcitonin?

This study was conducted to define the value of procalcitonin (PCT) levels in the differential diagnosis of abdominal familial Mediterranean fever (FMF) attacks from acute appendicitis. From October 2006 to January 2007, 28 FMF (12 males, 16 females) patients with acute abdominal attacks and 34 patients (18 males) with acute abdomen who underwent operation with the clinical diagnosis of acute appendicitis were consecutively enrolled in this study. FMF patients with concurrent infectious diseases were excluded. PCT values were measured by an immunofluorescent method using the B.R.A.H.M.S. PCT kit (B.R.A.H.M.S. Diagnostica, Berlin, Germany). Erythrocyte sedimentation rate (ESR), C-reactive proteins (CRP) and leucocyte levels were also noted. Mean disease duration in FMF patients was 9.6 ± 8.1 years (range 2–33 years) and all were on colchicine therapy with a mean colchicine dosage of 1.2 ± 0.4 mg/day. Among the operated patients, 5 were excluded: 3 patients had normal findings and 2 had intestinal perforation (PCT levels were 2.69 and 4.93 ng/ml, respectively) at operative and pathologic evaluation. There were no significant differences between the two groups with respect to gender and age (p was not significant (NS) for all). Acute phase reactants and PCT levels were increased in patients with FMF compared to patients with acute appendicitis (0.529[0.12 ± 0.96] vs 0.095 [0.01–0.80] p < 0.001, respectively). PCT levels higher than 0.5 ng/ml were found in 11% (3/28) of FMF patients compared to 62% (18/29) of acute appendicitis patients (p < 0.001). Our results suggest that PCT could be a useful test in the differentiation of abdominal FMF attacks from acute appendicitis, though it should not supplant more conventional investigations.     

Familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most frequent hereditary inflammatory disease characterized by self-limited recurrent attacks of fever and serositis. It is transmitted in an autosomal recessive pattern and affects certain ethnic groups mainly Jews, Turks, Arabs, and Armenians. FMF is caused by mutations in MEFV gene, which encodes pyrin. This protein is expressed mainly in myeloid/monocytic cells and modulates IL-1β processing, NF-κB activation, and apoptosis. A mutated pyrin probably results in uncontrolled inflammation. The most devastating complication of FMF is amyloidosis, leading to chronic renal failure. M694V homozygocity, male gender and the α/α genotype of serum amyloid A1 gene are the currently established risk factors for development of amyloidosis. Daily colchicine is the mainstay of the therapy for the disease, resulting in complete remission or marked reduction in the frequency and duration of attacks in most patients. It is also effective in preventing and arresting renal amyloidosis.     

The relation between familial Mediterranean fever and amyloidosis

Familial Mediterranean fever (FMF) is the most prevalent type of hereditary recurrent fever. Although the inflammatory attacks that characterize the disease may sometimes be debilitating, reactive amyloidosis remains the most serious manifestation of FMF. Daily treatment with colchicine can prevent both the attacks and amyloid deposition, but FMF-associated amyloidosis has not been eradicated and is still a cause of chronic renal failure in children and adults. The discovery of the gene responsible for FMF, Mediterranean fever gene (MEFV), and of associated mutations represents a major advance that now allows researchers to establish a strong, although nonexclusive association between one specific mutation, M694V, and the amyloid phenotype.     

Unilateral lymphocytic pleuritis as a manifestation of familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting predominantly populations surrounding the Mediterranean basin. It is the most prevalent hereditary periodic fever syndrome characterized mainly by recurrent and short attacks of fever and serositis (pleuritis, arthritis, peritonitis). Unilateral polymorphonuclear exudative pleuritis associated with fever has been reported as the solitary manifestation of the first FMF attack, in < 10% of patients. This case study describes a 30-year-old Greek man with recurrent episodes of lymphocytic exudative pleuritis associated with fever. After a thorough workup (clinical criteria and molecular genetic testing identifying homozygosity polymorphisms of the FMF gene), the diagnosis of FMF was established. Treatment with colchicine, 2 mg/d, eliminated FMF attacks. To our knowledge, this is the first well-documented case report of a patient with FMF presenting with a lymphocytic exudative pleural effusion.     

Relationship of serum vitamin D,D-dimer and uric acid levels with attacks in children with familial Mediterranean fever

Aim of the workFamilial Mediterranean fever (FMF) is the most common autoinflammatory disease that progresses with attacks of fever and serosal or skin inflammation. The first attacks typically begin during childhood and last for 12–72 h. The aim of this study was to determine the relationship of the serum 25-hydroxyvitamin D3(25(OH)D), D-dimer, and uric acid levels with attacks and subclinical inflammation in children with FMF.Patients and methodsA total of 178 patients with FMF recruited from the pediatric nephrology clinic were studied. Patients' characteristics, serum 25(OH) D, D-dimer, uric acid levels and other laboratory findings were obtained from patient files and/or hospital system records.ResultsThe age of the patients was 10.71 ± 3.94 (2.5–18) years, age at onset 8.7 ± 3.5 years and they were 95 females and 83 males (F:M 1.14:1). 38 had attacks. Symptoms during the attacks included fever in all children, abdominal pain in 93.3%, arthralgia in 75.8% and headache in 2.2%. The mean vitamin D level was 21.81 ± 11.97 ng/ml, median D-dimer 408.03 (111–3770) ng/ml and serum uric acid was 4.04 ± 1.27 mg/dl. Hypovitaminosis D was present in 86.5%. White blood cell count, C-reactive protein level, erythrocyte sedimentation rate, serum amyloid A, uric acid and D-dimer levels were higher in patients during attacks compared to those during attack-free periods (p = 0.001, p = 0.001, p = 0.001, p = 0.001, p = 0.022, and p = 0.001, respectively).ConclusionsHypovitaminosis D is frequent in FMF children and thus vitamin D supplementation is warranted. D-dimer and uric acid levels may be used as markers during follow-up of attacks.     

La fièvre méditerranéenne familiale

Familial Mediterranean Fever (FMF) is the most frequent monogenic auto-inflammatory disease. FMF is an autosomal recessive disease, which affects populations from Mediterranean origin and is associated with MEFV gene mutations encoding for the protein pyrin. Pyrin activation enhances the secretion of interleukin 1 by myelo-monocytic cells. Main features of the disease are acute attacks of serositis mainly located on the abdomen, less frequently on chest and joints, accompanied by fever and biological inflammatory markers elevation. Usually attacks last 1 to 3 days and spontaneously stop. A daily oral colchicine intake of 1 to 2 mg/day is able to prevent attack's occurrence, frequency, intensity and duration among most patients. Colchicine is also able to prevent the development of inflammatory amyloidosis, the most severe complication of FMF. This state of the art article will focus on the diagnosis of FMF, the treatment and an update on the pathophysiology including the recent described dominant form of MEFV-associated new auto-inflammatory diseases.     

Approach to the patients with inadequate response to colchicine in familial Mediterranean fever

Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1β) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages.     

Protracted arthritis in a Japanese patient with familial Mediterranean fever

The most common arthritic involvement in familial Mediterranean fever (FMF) is acute self- limiting monoarthritis which typically lasts for 72 h. Hip joint involvement is uncommon in FMF and can result either from a process specific to this disease or from a coexisting inflammatory joint disease. We describe a 37-year-old woman with FMF and right osteoarthritis secondary to congenital hip dislocation. Periodic fever with right coxalgia lasting for 6 months was treated using colchicine. Genetic analysis revealed homozygous mutation in the MEFV gene (L110P-E148Q/L110P-E148Q), confirming the FMF diagnosis. Although the clinical presentation and course of FMF arthritis are diverse, delineating these clinical patterns may help with early recognition and treatment to prevent destructive arthritis in FMF. Clinicians should consider the possibility of FMF development in unusual monoarthritis patients with recurrent febrile attacks.     

Uncommon clinical pattern of FMF: protracted febrile myalgia syndrome

Familial Mediterranean fever (FMF) is a genetic multisystem disorder of unknown etiology characterized by recurrent episodes of fever and pain due to acute inflammation of the peritoneum, synovia, or pleura. Up to 25% of patients with FMF report muscle pain. Myalgia may be a spontaneous pattern, exercise-induced pattern, or protracted febrile myalgia syndrome (PFMS). PFMS is characterized by severe paralyzing myalgia, high fever, abdominal pain, diarrhea, arthritis/arthralgia, and transient vasculitic rashes mimicking Henoch-Schonlein purpura. The episodes last for 4–6 weeks, except in those patients treated with corticosteroids. The PFMS may recur even under colchicine prophylaxis. We describe a 30-year-old pregnant Turkish woman with known FMF and under colchicine prophylaxis, with severe myalgia for 8 weeks, emphasizing the importance of a different clinical pattern of PFMS even in the absence of other symptoms.