Familial Mediterranean Fever Amyloidosis Research Articles

Abstract 26 — Clinical Characteristics of Familial Mediterranean: Fever in Hemodialysis Patients

Introduction Familial Mediterranean fever (FMF) is an inherited genetic disorder characterized by recurrent episodes of fever, serositis, arthritis, and skin rash. Uncontrolled disease can lead to amyloid A disposition, nephrotic syndrome and progressive renal failure. Recurrence of AA amyloidosis post kidney transplantation has been reported. Long-term colchicine therapy will reduce the FMF attacks and risk of AA amyloidosis. Although there is high prevalence of FMF in MENA region, the data of end stage renal disease (ESRD) in FMF is limited. We report our center experience. Method A retrospective chart review study was conducted at Tawam Hospital over 12 years (January 2010 to January 2023). We included adult ESRD on hemodialysis with FMF disease and studied their management outcomes. Descriptive analysis was used. Results 1900 ESRD patients were on hemodialysis during study period, and only two patients were diagnosed with FMF and renal amyloidosis. Case 1: A 60-year-old male patient from Syria who is known to have FMF and polycystic kidney disease leading to ESRD. He underwent successful LRD kidney transplantation in 2009. He was on mycophenolic acid: 540 mg, BID, prednisolone: 5 mg, tacrolimus: 1 mg am, 0.5 mg and colchicine 0.5 mg BID. He developed progressive renal allograft dysfunction with evidence of nephrotic syndrome. The renal biopsy revealed recurrence of AA amyloidosis due to FMF in kidney allograft in 2018. He had decline in renal function over years was initiated on hemodialysis on 2022. He developed two attacks of FMF peritonitis while on hemodialysis that responded well to steroid/colchicine therapy. Case 2: 48 years old male, from Egypt, known to have irritable bowel syndrome. He presented to our hospital with bilateral lower limb edema, and progressive shortness of breath for one month. Investigations revealed heavy proteinuria (8.98 g/g Creat) and acute kidney injury. Serology and autoimmune workup were negative. Kidney biopsy showed renal amyloidosis, and chronic tubulointerstitial nephritis with severe interstitial fibrosis (60%). History taken again and was positive for FMF in his uncle. Genetic study and clinical confirmed the diagnosis of FMF. He was started on colchicine, but developed ESRD within 8 months and initiated on hemodialysis. He had attacks of FMF. Conclusion Renal amyloidosis in FMF patient leads to progressive renal failure despite colchicine therapy. In our dialysis cohort over 12 years, only two FMF patients were identified. Colchicine therapy is required in ESRD-FMF in order to managed FMF attacks and prevent other organ AA amyloidosis.

Renal tubular and glomerular estrogen receptor ß levels are lower in lupus nephritis than in familial Mediterranean fever-associated renal amyloidosis.

Estrogen has been thought to play an essential role in the disease pathogenesis of systemic lupus erythematosus, which is 9-10 times more prevalent in the female population. It has been shown that irregular estrogen/estrogen receptor signaling pathways may contribute to the pathophysiology of various renal diseases. In this study, we compared renal estrogen receptors between lupus nephritis, familial Mediterranean fever-associated renal amyloidosis, ANCA-associated nephritis, and intact kidney to investigate their role in the pathophysiology of renal diseases. This study was designed as a retrospective cohort study. Thirty systemic lupus erythematosus patients with lupus nephritis, 12 familial Mediterranean fever amyloidosis and 10 ANCA-associated glomerulonephrites, and 14 individuals with normal renal histology were included in the study. Tubular estrogen receptor ß expression score was found to be significantly higher in the familial Mediterranean fever [5 (1-8)] group than in the lupus nephritis [0 (0-1)] (B = 1.385, OR = 3.996, CI %95 = 1.805-8.846, p = .001) and ANCA [4 (1-6.5)] (B = -1.431, OR = 0.239, CI 95% = 0.093-0.614, p = .003) groups. A significant correlation was found between serum creatinine values and tubular estrogen receptor ß expression score (OR = 0.565, CI 95% = 0.622-1.402, p < .0001). In ANCA-associated glomerulonephritis, a significant relationship was found between fibro cellular crescents in renal biopsy and glomerular estrogen receptor ß expression score (OR = 0.247, CI 95% = 0.11-0.999, p = .045) and tubular estrogen receptor ß expression score (OR = 0.282, CI 95% = -0.180-2.812, p = .026). This study showed that tubular estrogen receptor ß expression score was elevated in familial Mediterranean fever amyloidosis and correlated with serum creatinine levels and renal crescents.

Long-term results of kidney transplantation in patients with familial mediterranean fever.

Long-term kidney transplantation (KT) results in patients with familial Mediterranean fever (FMF)-related amyloidosis are not well studied. This study reviewed the long-term survival outcomes of FMF patients who underwent KT. We compared the outcomes of 31 patients who underwent (KT) for biopsy-proven amyloidosis secondary to FMF with 31 control patients (five with diabetes mellitus and 26 with nondiabetic kidney disease) undergoing KT between 1994 and 2021 at Başkent University Hospital. All data were recorded retrospectively from patients' files. THE MEDIAN AGE (QUARTILE DEVIATION: QD) at the time of KT in the FMF and control group were 31 (6.7) and 33 (11), respectively. The median follow-up period (QD) after KT was 108 (57) months in the FMF and 132 (72) months in the control group. In the FMF group, graft and patient survivals were 71% and 84% at 5 years and 45% and 48% at 10 years, respectively. In the control group, graft and patient survivals were 79% and 100% at 5 years and 63% and 71% at 10 years, respectively. Patient survival in the FMF group at 5 years was significantly lower than in the control group (p=.045). There was no statistically significant difference between the FMF and control groups in terms of graft and patient survival, and serum creatinine levels at 10 years. All patients were given triple immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and prednisolone. Three patients received anakinra and one received canakinumab in addition to colchicine treatment. One FMF patient also underwent heart transplantation due to AA amyloidosis. Of the FMF patients, 11 died during follow-up. We have found that the long-term outcome of KT in patients with FMF amyloidosis is numerically worse but not statistically different from the control group. However, short- and long-term complications still need to be resolved.

Plasminogen gene polymorphisms [c.924C>T and IVS 8+14 G>A] in periodontitis and familial Mediterranean fever: A case-control study.

The plasminogen (PLG) activation system plays an essential role in severe inflammation based diseases such as periodontitis, destructive membranous periodontal disease (ligneous periodontitis), familial Mediterranean fever (FMF), and amyloidosis. We have aimed to evaluate variations in PLG and the associations between PLG and MEFV genotypes in patients with FMF/ FMF-related secondary amyloidosis and periodontitis. A total of 247 individuals who were either diagnosed with FMF or systemically healthy were recruited to this human observational study with a cross-sectional design. All individuals were also diagnosed with periodontitis or periodontally healthy. Blood samples were obtained from patients with FMF and systemically healthy controls. Clinical periodontal indicators were recorded. All polymorphisms located in exons 6 and 8 of PLG and mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing. Genotypes and allele frequencies of PLG and MEFV were detected and tested by the Hardy-Weinberg equilibrium. Serum levels of amyloid A (SAA), high-sensitive C-reactive protein (hs-CRP), PLG, and salivary PLG levels were determined by using enzyme-linked immunosorbent assay (ELISA). Two polymorphisms were identified in PLG: G to A polymorphism on the 14th nucleotide of intron 8 and C to T polymorphism on the 924th nucleotide of the coding region (IVS 8+14 G>A and c.924C>T, respectively). In IVS 8+14 G>A polymorphisms, wild-type genotype: GG, heterozygote genotype: GA and homozygote genotype: AA. In c.924C>T polymorphism, wild-type genotype: CC, heterozygote genotype: CT and homozygote genotype: TT. The frequency of the heterozygous polymorphisms of PLG was significantly increased (17.6%) in FMF patients with periodontitis (p = .027). A large proportion of the test group that was heterozygous for MEFV-R202Q also had heterozygous PLG polymorphisms. Remarkable exacerbation in periodontal parameters was observed in patients with FMF and amyloidosis. SAA and hs-CRP levels were significantly correlated with salivary PLG levels in patients with periodontitis and heterozygous PLG. The current study describes IVS 8+14 G>A (rs2295368) and c.924C>T (rs1380916375) polymorphisms for the first time in the periodontal literature, which might play an important role in the pathogenesis of periodontitis, FMF, or amyloidosis. The elucidation of PLG polymorphisms is beneficial from a public health perspective by increasing the quality of life in these patients and reducing the mortality and morbidity associated with inflammatory diseases such as periodontal disease, FMF, and FMF-related amyloidosis.

Colchicine, terug van nooit weggeweest

Colchicine: ancient and brand new Colchicine is an alkaloid initially extracted from an autumn crocus. Its use dates back to the 6th century BC, with the first indication being gout. In the last 50 years, further insights into its mechanism of action emerged along with an expansion of the number of indications. Colchicine inhibits the chemotaxis of leukocytes. Recently, it was discovered that in addition to its action on the microtubules, there is also an effect on the NLRP3 inflammasome. Colchicine has a narrow therapeutic index and caution is advised in patients with renal and hepatic failure. It’s a CYP3A4 and P-gp substrate. Therefore, concomitant use with CYP3A4 and P-gp inhibitors is contraindicated given the greatly increased risk of toxicity. Its most frequent side effect is diarrhea and severe intoxications can be lethal. The main rheumatologic indications are the treatment of gout in the acute phase, attack prevention and amyloidosis in familial Mediterranean fever, and ulcerations in Behçet’s disease. The cardiovascular use of colchicine in acute and relapsing/chronic pericarditis has been well established. Recent studies also show a beneficial effect in case of acute and chronic coronary artery disease. Additional studies for the implementation of colchicine for these indications are ongoing.

Семейная средиземноморская лихорадка, женская и мужская фертильность: литературный обзор

Семейная средиземноморская лихорадка (CCЛ) - моногенное наследственное аутовоспалительное заболевание, характеризующееся периодически повторяющимися приступами лихорадки, серозитами разной локализации, артритами, эризипелоидоподобным высыпанием. Хотя ССЛ болеют преимущественно представители популяций восточно-средиземноморского происхождения (турки, армяне, арабы, евреи-сефарды), в наши дни болезнь регистрируется по всему миру, что связано с непрерывными миграционными процессами. Потенциальные осложнения ССЛ (фиброз и амилоидоз) и их лечение колхицином могут повлиять на репродуктивную систему больных либо путем обструкции маточных труб, либо через избыточное образование дефектных сперматозоидов и ооцитов, либо вследствие овариальной/тестикулярной недостаточности. Амилоидоз с преимущественным отложением амилоида в яичниках и яичках может приводить к женскому и мужскому бесплодию. У мужчин колхицин в редких случаях индуцирует олиго/азооспермию. У женщин основными причинами бесплодия в прошлом считались дисовуляция и перитонеальная адгезия. В последние годы ситуация с фертильностью значительно улучшилась благодаря применению колхицина. В обзоре обобщается текущая информация о взаимосвязи женской и мужской фертильности с ССЛ и приемом колхицина; излагаются современные подходы к восстановлению репродуктивной функции при бесплодии. Акцент сделан на аспектах безопасности терапии, основные положения которой представлены в клинических рекомендациях по лечению ССЛ Европейской антиревматической лиги (EULAR,2016). Familial Mediterranean fever (FMF) is a monogenic inherited autoinflammatory disease characterized by recurrent episodes (attacks) of fever, serositis of different localization, arthritis, erysipelaslike rashes. Eastern Mediterranean persons (especially Turks, Armenians, Arabs, Sephardic Jews) are most frequently affected. Nowadays the disease is registered throughout the world because of migration processes. Potential complications of FMF (fibrosis and amyloidosis) and their treatment with colchicine may affect the reproductive system either by salpinx obstruction causing mechanical infertility, or by excessive formation of defective sperm and oocytes, either due to ovarian /testicular insufficiency. Amyloidosis can lead to female and male infertility with amyloid preponderance in the ovaries and testicles. Colchicine rarely induces oligo/ azoospermia in men. In women, disovulation and peritoneal adhesion were the main causes of infertility in the past. In recent years, the fertility situation has improved considerably due to the use of colchicine. The review summarizes current information on the relationship between female and male fertility with FMF and colchicine; modern approaches to restoring reproductive function in infertility are outlined. The focus is on the aspects of the safety of therapy, the main provisions of which are presented in the clinical recommendations for treatment of the FMF of the European Anti-Rheumatic League (EULAR, 2016).

Amyloid storm: acute kidney injury and massive proteinuria, rapidly progressing to end-stage kidney disease in AA amyloidosis of familial Mediterranean fever.

Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Soluble TREM-1 Levels in Familial Mediterranean Fever Related AA-Amyloidosis

ABSTRACT Objectives: Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is a monocyte and neutrophil receptor functioning in innate immunity. TREM-1 activity has been studied in various autoimmune diseases such as RA and SLE but there is no data in autoinflammatory pathologies. We studied soluble TREM-1 (sTREM-1) activity in Familial Mediterranean Fever (FMF) cases to evaluate the clinical role of TREM-1 in amyloidosis. Methods: The study includes 62 patients with FMF (42 with amyloidosis) who are regular attendees of a tertiary center for autoinflammatory diseases. For control purposes, 5 patients with AA amyloidosis secondary to other inflammatory diseases, and 20 healthy individuals were also included. Soluble TREM-1 levels were measured using enzyme-linked immunosorbent assay (ELISA). All FMF patients were in an attack-free period during the collection of the blood samples.Results: Soluble TREM-1 levels were found to be significantly higher in the FMF amyloidosis group compared to FMF without amyloidosis group and healthy controls (p = .001 and 0.002). Nevertheless, this difference between sTREM-1 levels was not found among FMF amyloidosis and other AA amyloidosis groups (p = .447) as well as between only FMF patients and healthy controls (p = .532). Soluble TREM-1 levels were found in correlation with creatinine and CRP in the FMF patient group regardless of their amyloidosis diagnosis (r = 0.314, p = .013; r = 0.846, p < .001).Conclusion: TREM-1 seems to be related to renal function rather than disease activity in FMF. Its role as an early diagnostic marker of amyloidosis in FMF complicated with AA amyloidosis should be tested in larger patient groups.

Amyloid A Amyloidosis After Renal Transplantation: An Important Cause of Mortality.

There are limited data on the outcome of transplant recipients with familial Mediterranean fever (FMF)-associated AA amyloidosis. The aim of the present study is to evaluate demographic, clinical, laboratory, and prognostic characteristics and outcome measures of these patients. Eighty-one renal transplant recipients with FMF-associated AA amyloidosis (group 1) and propensity score-matched transplant recipients (group 2, n = 81) with nonamyloidosis etiologies were evaluated in this retrospective, multicenter study. Recurrence of AA amyloidosis was diagnosed in 21 patients (group 1a), and their features were compared with 21 propensity score-matched recipients with FMF amyloidosis with no laboratory signs of recurrence (group 1b). The risk of overall allograft loss was higher in group 1 compared with group 2 (25 [30.9%] versus 12 [14.8%]; P = 0.015 [hazard ratio, 2.083; 95% confidence interval, 1.126-3.856]). Patients in group 1 were characterized by an increased risk of mortality compared with group 2 (11 [13.6%] versus 0%; P = 0.001 [hazard ratio, 1.136; 95% confidence interval, 1.058-1.207]). Kaplan-Meier analysis revealed that 5- and 10-year patient survival rates in group 1 (92.5% and 70.4%) were significantly lower than in group 2 (100% and 100%; P = 0.026 and P = 0.023, respectively). Although not reaching significance, overall, 5- and 10-year graft survival rates (57.1%, 94.7%, and 53.8%, respectively) in group 1a were worse than in group 1b (76.2%, 95%, and 77.8%, respectively; P = 0.19, P = 0.95, and P = 0.27, respectively). AA amyloidosis is associated with higher risk of mortality after kidney transplantation. Inflammatory indicators should be monitored closely, and persistent high levels of acute-phase reactants should raise concerns about amyloid recurrence in allograft.

Long-term Results of Kidney Transplantation in Patients With Familial Mediterranean Fever and Amyloidosis

IntroductionAmyloid A amyloidosis is most commonly caused by familial Mediterranean fever (FMF) in Turkey. Amyloidosis secondary to FMF is an important cause of end-stage renal failure, and kidney transplantation (KT) in these cases can be complicated, with long-term results oftentimes inferior compared with organ transplant in patients without FMF. The present study aims to show the long-term results of patients with secondary amyloidosis caused by FMF undergoing KT . MethodsWe enrolled 27 patients with a history of FMF amyloidosis undergoing KT and a control group of 614 patients undergoing KT between 2005 and 2018 at Ankara University Medical School. All data were recorded retrospectively from patients files. ResultsTwenty-two patients (81.5%) were treated with triple immunosuppressive therapy consisting of mycophenolate mofetil, tacrolimus, and a steroid; 5 patients (18.5%) were treated with tacrolimus, azathioprine, and prednisolone. Acute cellular rejection was seen in 3 patients (11.1%), and acute cellular- and antibody-mediated rejection occurred in 1 patient (3.7%). During the follow-up period, graft loss due to acute cellular rejection was observed in only 1 patient. One patient was lost to follow-up.

Colchicine's Effects on Electrocardiographic Parameters in Newly Diagnosed Familial Mediterranean Fever Patients : Colchicine may have Favourable Effects on Parameters Related to Ventricular Arrhythmias in New Diagnosed Familial Mediterranean Fever.

Colchicine may prevent both recurrent serositis attacks and secondary amyloidosis in familial Mediterranean fever (FMF). Furthermore, colchicine may decrease the frequency of atrial fibrillation in some groups of patients without FMF. However, there is no study that evaluates the effect of colchicine on arrhythmogenic electrocardiographic indices in FMF. In this study, we evaluated the impact of 1year of colchicine treatment on atrial and ventricular arrhythmogenic electrocardiographic (ECG) parameters in newly diagnosed FMF patients. We enrolled 28newly diagnosed FMF (20female, mean age 31.4 ± 8.2years) patients who fulfilled the modified Tel Hashomer criteria. Electrocardiographic, demographic and laboratory parameters were obtained at the first visit and at the end of the 1‑year colchicine treatment. Herein, we assessed Pwave dispersion (Pd) for atrial arrhythmia risk and peak-to-end interval of Twave (Tp-E), Tp-E/QT, Tp-E/QTc values for ventricular arrhythmia risk. Colchicine treatment significantly decreased Tp-E and Tp-E/QT values (p = 0.02 and p = 0.01, respectively) by the end of the 1‑year treatment. However, Pd values did not change with treatment. Colchicine treatment may have afavourable effect on ventricular repolarisation indices that relate to ventricular arrhythmia and sudden death.

Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever?

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. The disease characteristics may vary in different age groups. In this study, we aimed to compare disease characteristics and treatment compliance according to the age of pediatric FMF patients. This is a single-center, cross-sectional study. Between August and October 2016, patients who were diagnosed with FMF, participated to the study. 378 pediatric FMF patients were enrolled in the study. Among those, age at symptom onset was ≤ 5years in 69%, 6-11years in 26% and ≥ 12years in 5%. Patients older than 12years old at symptom onset, had significantly less frequent fever attacks than the patients from other age groups. Patients younger than 5years old at symptom onset had significantly higher international severity scoring system for FMF (ISSF) than other patients. And M694V homozygosity was significantly more frequent in patients with younger age at symptom onset. Patients younger than 5years old were using their drugs more regularly than the other age groups (p = 0.002). Drug compliance was 90.5% in patients ≤ 5 years, 64.4% in patients 6-11 years, 58.3% in patients ≥ 12years. The disease characteristics of FMF may differ between patients with different age at symptom onset. Younger age at disease onset seems to be related with more severe course; thus these patients should be followed-up more closely. In addition, treatment compliance which is critical for prevention of amyloidosis in FMF should be questioned especially in adolescent patients.

Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis

Background: Colchicine is the mainstay of the treatment of familial Mediterranean fever (FMF). However, 10% of FMF patients do not respond well to colchicine. Efficacy of interleukin (IL)-1 inhibitors in reducing attacks have been demonstrated in colchicine-resistant FMF (crFMF) patients recently. Colchicine is still the only approved drug for the prevention of amyloidosis in FMF and utility of IL-1 inhibitors in crFMF cases who already has amyloidosis remain to be elucidated. Herein, we evaluated efficacy and safety of IL-1 inhibitors in patients with crFMF-associated AA amyloidosis in a relatively large single center study.Methods: Medical records of FMF patients complicated with AA amyloidosis in our dedicated FMF center were retrospectively reviewed and those patients who ever treated with IL-1 inhibitors were enrolled into the study. Patient global, physician global assessments (on 0–10 cm visual analog scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine and 24-h urinary protein excretion values for each visit were recruited from computer-based hospital records. Treatment response of patients were assessed with clinical symptoms, serum albumin, CRP and ESR values. Renal outcome parameters were analyzed on those not receiving renal replacement therapy.Results: Seventeen patients were identified with crFMF-amyloidosis that ever treated with IL-1 inhibitors. Background colchicine therapy was continued in all patients in maximal-tolerated dose along with IL-1 inhibitors. All patients benefit from IL-1 antagonists assessed by patient and physician global assessments. Inflammatory markers, CRP and ESR, were significantly reduced in all and normalized in 12 out of 17 patients. More importantly, the amount of proteinuria was remarkably improved following IL-1 inhibitor therapy (1606 mg/day to 519 mg/day, p = .008). Both anakinra and canakinumab were well-tolerated without severe side effects. All patients were initially treated with anakinra but switched to canakinumab in seven patients (one leukopenia, four injection site reaction, two inefficacy).Conclusion: We evaluated the clinical and laboratory responses to IL-1 inhibitors in crFMF-associated amyloidosis patients. We found significant decreases in CRP, ESR and proteinuria after IL-1 inhibitor therapy. This study confirmed that IL-1 inhibitors are effective for controlling attacks and inflammatory activity in FMF patients complicated with AA amyloidosis. Moreover, they reduce or stabilize amount of proteinuria and preserve renal function in short-term follow-up. Prolonged prospective clinical trials are warranted to assess their long-term efficacy in this particular patient group.

Serum, salivary, and tissue levels of plasminogen in familial Mediterranean fever, amyloidosis, and chronic periodontitis.

There are no published studies regarding the role of the plasminogen (PLG) system in familial Mediterranean fever (FMF), FMF-associated secondary amyloidosis, or chronic periodontitis (CP), although recent limited data have focused on the association between FMF and chronic periodontitis. Therefore, the aim of this study was to evaluate the serum, salivary, and gingival tissue levels of PLG in patients with CP, FMF, and amyloidosis. The study population included 122 patients with FMF (only FMF, and FMF and amyloidosis and 128 individuals who were systemically healthy controls. Blood and salivary samples were obtained from the cases and controls, and clinical periodontal parameters were recorded. Serum and salivary PLG levels were assessed. The gingival tissue samples of the case and control groups were analyzed histopathologically and immunohistochemically for amyloid deposition and PLG. The amyloidosis group had significantly more severe clinical periodontal parameters than those of the FMF and systemically healthy groups (P<0.05). Salivary levels of PLG were significantly higher in the FMF and amyloidosis groups compared with those in the control group (P<0.001). The FMF with periodontitis and amyloidosis with periodontitis groups had higher salivary PLG levels compared with those in the CP group. Serum and salivary PLG levels were significantly associated with the clinical periodontal parameters in the FMF group. The amyloidosis cases had hyperplasia, severe inflammation, and activation of the gingiva. The PLG system could play an important role in inflammatory diseases, such as chronic periodontitis, FMF, and FMF-associated secondary amyloidosis.

Familial Mediterranean Fever Is Associated With Increased Mortality After Kidney Transplantation—A 19 Years' Single Center Experience

Current data regarding the outcome of kidney transplantation in patients with familial Mediterranean fever (FMF) who reach end-stage renal disease (ESRD) due to reactive amyloidosis A (AA) are scarce and inconclusive. The outcomes of 20 patients with FMF and biopsy-proven AA amyloidosis that were transplanted between 1995 and 2014 were compared with 82 control patients (32 with diabetes mellitus and 50 with nondiabetic kidney disease). Major outcome data included overall patient and graft survivals. During a mean overall follow-up of 116.6 ± 67.5 months 11 patients (55%) with FMF died versus 26 patients (31%) in the control group. Median time of death for patients with FMF was 61 months (range, 16-81) after transplantation. Estimated 5-year, 10-year, and actuarial 15-year overall patients survival rates were 73%, 45%, and 39%, respectively, for patients with FMF, versus 84%, 68% and 63%, respectively, for the control group (P = 0.028). FMF was associated with more than twofold increased risk for death after transplantation, and with a threefold increased risk for hospitalization because of infections during the first year. Infections and cardiovascular disease were the cause of death in the majority of patients with FMF. Overall graft survival was similar between the groups. Recurrence of AA amyloidosis was diagnosed in 2 patients during the first year after transplantation. FMF is associated with increased risk of mortality after kidney transplantation.

Late ventricular potentials in familial Mediterranean fever with and without AA amyloidosis.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by episodic and chronic inflammation that may lead to both accelerated coronary atherosclerosis and cardiac AA amyloidosis. We hypothesized that late ventricular potentials (LPs), an established electrocardiographic susceptibility marker of ventricular arrhythmias, will be more common in FMF than in the adjusted normal population due to these two types of inflammation-associated cardiac effects. Therefore, we aimed to evaluate the occurrence of LPs in FMF patients with and without amyloidosis. Signal-averaged electrocardiography was performed in consecutive patients with FMF using the Frank corrected orthogonal lead system. At least 200 consecutive beats were digitally recorded and averaged, and the presence of LPs was determined according to acceptable thresholds. There were 54 patients with colchicine-treated FMF, of whom 14 had biopsy-proven AA amyloidosis. None of the uncomplicated FMF patients and 2 of the 14 FMF amyloidosis patients had abnormal or borderline LPs. Based on LPs as a susceptibility marker for arrhythmia, FMF patients, including the large majority of FMF patients with amyloidosis, are seemingly not at an increased risk to develop arrhythmias.

R202Q/M694V as novel MEFV gene mutations in chronic periodontitis and familial Mediterranean fever.

Familial Mediterranean fever (FMF) and chronic periodontitis are inflammatory diseases leading to an increase in the number of inflammasomes. To date, no published studies have reported on mutations in the Mediterranean fever (MEFV) gene in patients with chronic periodontitis, although the roles of MEFV gene mutations in FMF and FMF-associated amyloidosis (FMF-A) are well known. Therefore, the aim of this study was to evaluate the frequencies of MEFV gene mutations and serum amyloid A (SAA) and high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic periodontitis, FMF and FMF-A. The study population included 122 patients with FMF and 128 subjects who were systemically healthy. Clinical periodontal parameters, including the plaque index, gingival index, probing pocket depth, clinical attachment level and percentage of bleeding on probing were recorded. Blood samples were obtained from patients with FMF and systemically healthy controls, and all mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing, which is the gold standard. SAA and high-sensitive CRP levels were also assessed. Mean gingival index, percentage of bleeding on probing, probing pocket depth and clinical attachment level, and the levels of SAA and hs-CRP were higher in the FMF-A group than those in the FMF and control groups. The two most relevant mutations in patients with FMF were heterozygous M694V (46.2%), and heterozygous R202Q (32.7%). The frequencies of the homozygous M694V and R202Q mutations in the FMF-A group were 53.8% and 46.1%, respectively. The complex R202Q/M694V homozygous state led to an increased risk of chronic periodontitis (odds ratio: 3.6), and FMF-A (odds ratio: 7.6). This is the first study to report the R202Q mutation in patients with periodontitis. Furthermore, the MEFV gene-mediated inflammatory pathway increased serum acute phase reactants, and the changes in the R202Q and M694V could play a role in inflammatory-genetic diseases, such as FMF, FMF-associated amyloidosis and chronic periodontitis.

Compliance to colchicine treatment and disease activity in Familial Mediterranean Fever (FMF) patients in Middle/Black Sea Region of Turkey (in Çorum region)

Background and question Colchicine is the gold standard treatment for prevention of inflammatory attacks and prevention of reactive amyloidosis in FMF. However, noncompliance to colchicine treatment is common among FMF patients. On the other hand, the disease may not be controlled in some patients despite use of full dose colchicine. In this study, we aimed to investigate the rates of disease control, compliance to colchicine treatment, and need for an additional treatment despite use of full dose colchicine in patients with FMF in Corum region where FMF is common in Turkey.

Predictors of AA amyloidosis in familial Mediterranean fever.

The aim of the study was to evaluate the clinical and genetic predictors of AA amyloidosis in patients with familial Mediterranean fever (FMF). We retrospectively studied 170 Armenian patients who were admitted to the two tertiary centers in 2003-2014. The diagnosis of amyloidosis that was suspected clinically (new proteinuria or nephrotic syndrome) was confirmed histologically. Screening for MEFV gene mutations was performed in 70 patients. The most common genotype was M694V/M694V (in 36% of patients). Biopsy-proven AA amyloidosis was found in 102 (60%) of 170 patients. AA amyloidosis was diagnosed in 17 (68%) of 25 patients with homozygous M694V mutation, 17 (53%) of 32 patients with heterozygous M694V allele and 4 (31%) of 13 patients with other MEFV gene mutations. The M694V homozygosity and heterozygosity were associated with increased risk of AA amyloidosis, but this association did not reach statistical significance (odds ratio 2.43; 95% CI 0.87-6.76, and 3.33; 0.91-12.1, respectively). Male gender, early onset of disease, severity of FMF, frequent attacks, peritonitis, pleuritis and erysipelas-like erythema also did not predict AA amyloidosis development. Recurrent arthritis was the only clinical finding that was significantly associated with AA amyloidosis (odds ratio 2.28; 95% CI 1.17-4.42). Involvement of the joint synovial membrane, that is capable of active serum amyloid A production, is the main predictor of renal amyloidosis in FMF.

Assessment of renal involvement in patients with familial Mediterranean fever: a clinical study from Ardabil, Iran.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent episodes of painful inflammation in the abdomen, chest or joints. The association between FMF and non-amyloid glomerulopathies are unusual. In this study, we describe our experiences and observations about renal involvement in patients with FMF. A total of 108 patients with FMF was enrolled in the study. Twelve patients with FMF were referred to the Nephrology Service, for evaluation and assessment of the degree of renal involvement. All the 12 patients underwent percutaneous ultrasound-guided renal biopsies and genetic analysis. On microscopic examination of the kidney specimens, six patients were found to have amyloidosis, five focal segmental glomerulosclerosis and one patient membranoproliferative glomerulonephritis. It seems that in patients with FMF and renal amyloidosis, the response to treatment with colchicine is excellent, but in patients with FMF and focal segmental glomerulosclerosis, the response to treatment with colchicine is poor. We present an evidence-based algorithm, constructed based on literature review, to aid decision making in management of renal involvement in patients with FMF. The results of our study suggest that in patients with FMF and renal involvement, non-amyloid renal lesions should be considered in the differential diagnosis in addition to amyloidosis.