Familial Mediterranean Fever After Cord Blood Transplantation for Familial Hemophagocytic Lymphohistiocytosis.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder accompanied by periodic fever and sterile serositis. We report a 5-year-old boy with FMF, who underwent second unrelated cord blood transplantation (CBT) for recurrent familial hemophagocytic lymphohistiocytosis. Periodic attacks of fever and abdominal pain started 6 months after CBT. He was diagnosed with FMF according to the Tel-Hashomer criteria and treated successfully with colchicine. Genetic testing showed heterozygous p.E148Q mutation in the MEFV gene from both donor and recipient cells. Several CBT-related factors including use of an immunosuppressant can potentially be involved in the pathogenesis of FMF in our patient.

Canakinumab treatment in kidney transplant recipients with AA amyloidosis due to familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent serosal inflammation with fever, which can result in amyloid deposition. Anti-interleukin-1 drugs emerge as a therapeutic option for colchicine-resistant patients. In this study, we aimed to document our experience with canakinumab use in kidney transplant recipients who developed AA amyloidosis due to FMF. METHODS: A total of nine patients with FMF amyloidosis treated with canakinumab were enrolled. Laboratory and clinical data were collected from the patient files, electronic database of the hospital and with interviews. RESULTS: Five of the patients were male and four were female (median age: 33, range: 27-62 years). All of the patients had rapid or gradual disappearance of FMF attacks. The following changes in the laboratory parameters were observed before and after the treatment: C-reactive protein: 18.31 ± 13.58 mg/L vs 9.98 ± 11.66 mg/L, creatinine clearance: 45.27 ± 21.5 mL/min vs 50.71 ± 22.48 mL/min, and 24-hour proteinuria: 2381.8 ± 3910.4 mg vs 710.0 ± 1117.5 mg; there were no statistically significant differences on those parameters. One patient developed a reaction to injection while another showed symptoms of Cytomegalovirus pneumonia. CONCLUSION: Canakinumab can be considered as a safe and efficient drug in preventing the FMF attacks in kidney transplant recipients.

Atypical familial Mediterranean fever developed in a long-term hemodialysis patient.

Familial Mediterranean Fever (FMF) is usually an autosomal recessive autoinflammatory disease characterized by recurrent attacks of fever and serositis. FMF develops before the age of 20 years in 90% of patients. It has intervals of 1 week to several years between attacks, which leads to renal dysfunction-amyloidosis. We report a case of atypical FMF that developed in a long-term hemodialysis patient. A 65-year-old Japanese female undergoing hemodialysis for 32 years was referred to our hospital with a fever of unknown origin (FUO) following cervical laminoplasty. The fever occurred as recurrent attacks accompanied by oligoarthralgia of the left hip and knee. We suspected FMF because of recurrent self-limited febrile attacks, although the patient showed atypical clinical features such as late-onset and highly frequent attacks. After receiving treatment, she achieved a complete response to colchicine. Therefore, a diagnosis of FMF was made based on the Tel-Hashomer criteria, which was confirmed by genetic testing. The case suggests that FMF may be of note in long-term hemodialysis patients developing FUO.

Cold Exposure Related Fever with an Mediterranean Fever (MEFV) Gene Mutation.

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease characterized by recurrent fever with serosal inflammation. We experienced a 53-year-old male who had been suffering from periodic attacks with slight fever and myalgia which were mainly triggered by cold exposure in winter. Although his clinical course did not satisfy the criteria for familial Mediterranean fever, heterozygous E148Q/M694I mutation in the Mediterranean fever (MEFV) gene was detected. Further attacks were prevented by treatment with colchicine. Attention should therefore be paid to the possibility of atypical FMF symptoms, which should be accurately diagnosed by genetic analyses to prevent the development of amyloidosis.

Avaliação da frequência e aspectos dos ataques de pacientes com resistência à colchicina em febre familiar do Mediterrâneo (FFM) / Evaluation of frequency and the attacks features of patients with colchicine resistance in FMF

Introdução: Colchicina é a viga-mestra para o tratamento de FFM, que é uma doença autoinflamatória com polisserosite recidivante como principal manifestação. Apesar de doses diárias de 2 mg ou mais/dia, aproximadamente 5%-10% dos pacientes continuam a sofrer de seus ataques. Neste estudo, objetivamos investigar os aspectos da depressão e dos ataques em pacientes com FFM apresentando resistência à colchicina (RC). Pacientes e Métodos: Em pacientes com FFM, RC foi definida como dois ou mais ataques nos últimos seis meses, quando em medicação com colchicina 2 mg/dia. Dezoito pacientes (nove mulheres e nove homens) foram recrutados no grupo RC e 41 pacientes no grupo de controle (29 mulheres/12 homens). Foram avaliados os achados demográficos, clínicos e laboratoriais, a fidelidade ao tratamento e os escores do Beck Depression Inventory (BDI). Resultados: A idade de surgimento da FFM foi significativamente menor no grupo RC (12,3 anos vs. 16,9 anos, P = 0,03). A duração da doença foi maior no grupo RC (p = 0,01). Dores abdominais e nas pernas em decorrência do exercício foram significativamente mais frequentes no grupo RC versus controles (83% vs. 51%; p = 0,02 e 88% vs. 60%; p = 0,04, respectivamente). Pacientes com escores BDI > 17 pontos foram mais frequentes no grupo RC versus controles (50% vs. 34,1%; p < 0,001). Discussão: Verificamos que: (1) a idade do surgimento da doença foi mais baixa e (2) a duração da doença foi maior no grupo RC. Ataques pleuríticos, hematúria e proteinúria foram mais frequentes em pacientes com RC. Propomos que a depressão é fator importante a ser levado em consideração na sensibilidade à RC. .

Introduction: Colchicine is the mainstay for the treatment of FMF, which is an auto-inflammatory disease mainly with relapsing polyserositis. Despite daily doses of 2 mg or more each day, approximately 5% to 10% of the patients continue to suffer from its attacks. In this study, we aimed to investigate the depression and attack features in patients with FMF who have colchicine resistance (CR). Patients e Methods: CR was defined for FMF patients with 2 or more attacks within the last 6 months period while using 2 mg/day colchicine. Eighteen patients (9 Female/9 Male) were enrolled into the CR group and 41 patients were enrolled into the control group (12 Male/29 Female). Demographic, clinical e laboratory findings, treatment adherence, and the Beck Depression Inventory (BDI) scores were evaluated. Results: The age of onset of FMF was significantly lower in the CR group (12.3 yrs vs. 16.9 yrs, P = 0.03). Disease duration was longer in the CR group (P = 0.01). Abdominal and leg pain due to exercise were significantly more frequent in the CR group versus controls (83% vs. 51%; P = 0.02 e 88% vs. 60%; P = 0.04, respectively). Patients with BDI scores over 17 points were more frequent in the CR group compared to controls (50% vs. 34.1%; P < 0.001). Discussion: We found that: (1) the age of disease onset was lower and (2) the disease duration was longer in CR group. Pleuritic attacks, hematuria e proteinuria were more frequent in CR patients. We propose that depression is an important factor to consider in the susceptibility to CR. .

Diagnostic criteria of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, mainly affecting ethnic groups living at Mediterranean basin. FMF is characterized by recurrent, self-limited episodes of fever and serositis. The diagnosis is difficult in the presence of atypical signs, which may result in significant delay in initiating treatment. As autoinflammatory diseases may have overlapping symptoms, strict diagnostic criteria are essential. Since the discovery that mutations in the gene MEFV underlie FMF, molecular genetic testing has been used as a diagnostic adjunct, especially in atypical cases. However, despite progress in the understanding of FMF disease mechanisms during the past 15 years; the diagnosis is still based on clinical criteria. Several sets of diagnostic criteria have been proposed and used. Existing diagnostic criteria should be modified to include genetic data, and need to be more widely validated.

Periodic fever as the manifestation of primary Sjogren's syndrome: a case report and literature review.

A 56-year-old male had periodic fever for 5 years and suffered from auditory hallucination and hearing impairment for 3 years. Xerostomia, xerophthalmia, elevated anti-SSA/Ro tilter, positive Schirmer's test, and lymphocyte infiltrate of mucoserous gland in lip biopsy of this case confirmed the diagnosis of primary Sjogren's syndrome (pSS). We review literature for fever and neuropsychiatric involvement in pSS case series. Though fever is present in 6-41 % pSS cases, periodic fever has not been reported. Auditory hallucination was rare in cases with pSS. The literature review alerts clinicians that fever and neurological manifestations were not uncommon in pSS cases.

Autoinflammatory syndromes.

There has been an expansion of the autoinflammatory syndromes due to the discovery of new diseases related to mutations in genes regulating the innate immune system and the knowledge gained from these diseases as applied to more common nongenetic inflammatory conditions. Autoinflammatory syndromes are characterized by unprovoked (or triggered by minor events) recurrent episodes of systemic inflammation involving various body systems, which are often accompanied by fever. Inflammation is mediated by polymorphonuclear and macrophage cells through cytokines, particularly interleukin-1. This article reviews the clinical approach to patients with suspected autoinflammatory syndromes, several of the main and new (mostly genetics) syndromes, advances in treatment, and prognosis.

Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases.

PURPOSE OF REVIEW: The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. RECENT FINDINGS: IL-1ß is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1ß release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1ß release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). SUMMARY: Caspase 1 activation and IL-1ß release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.

Presentation of familial Mediterranean fever in a heterozygous MEFV mutation triggered by immunosuppressive therapy for myelodysplastic syndrome.

Familial Mediterranean fever (FMF) is a recessively inherited disease characterized by recurrent episodes of systemic inflammation. The cause of this disease is the mutations affecting both the alleles of MEFV gene. We describe here a case in a heterozygous MEFV mutation complicated with myelodysplastic syndrome (MDS). Clinical symptoms and the effectiveness of colchicines in this patient are typical for FMF. The first attack of FMF in this patient was observed during immunosuppressive therapy for MDS. This case suggests the possibility that certain immunosuppressants may trigger FMF attack in asymptomatic cases carrying MEFV heterozygous mutation.

Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease.

BACKGROUND: Worldwide, familial Mediterranean fever (FMF) is the most common autoinflammatory disease. It has been suggested that environmental factors affect the phenotype as some patients do not develop the complication of secondary amyloidosis. OBJECTIVE: To analyse whether disease severity in Turkish children with FMF, living in Turkey and Germany is different. PATIENTS AND METHODS: A total of 55 Turkish children living in Turkey were compared with 45 Turkish children born and raised in Germany. Mean age among the group from Turkey and Germany was 42.2 and 44.29 months, respectively. M694V was the leading mutation in both groups. The severity scores were compared with two scoring systems, modified according to published paediatric data for dosage. RESULTS: There was no significant difference between the mean C-reactive protein and erythrocyte sedimentation rate levels of the two groups. According to the modified Sheba Center score, 78.2% of patients from the group living in Turkey had a severe course compared with 34.1% from the group living in Germany. The modified score of Pras et al also showed more severe disease in the patients from Turkey. The difference between the two groups for both scoring systems were significant (both p<0.05). CONCLUSIONS: We believe the modified scores that we introduce can be widely used for children. Our results suggest that the environment affects the phenotype of a monogenic disease of the innate inflammatory pathway.

Fiebre mediterránea familiar: una afección frecuentemente subdiagnosticada / Febre mediterrânea familiar: uma afecção frequentemente subdiagnosticada

La fiebre mediterránea familiar (FMF) es una enfermedad inflamatoria crónica, hereditaria, de herencia autosómica recesiva, causada por mutaciones en el gene denominado MEFV. Se caracteriza por episodios recurrentes de fiebre e inflamación multisistémica. Se trata de una enfermedad frecuente en descendientes de poblaciones mediterráneas, del norte de África, Israel, Turquía, Armenia y países árabes. Se presenta el caso de un paciente, descendiente de armenios, con semiología y evolución características. Se analiza el diagnóstico, pronóstico, tratamiento y el asesoramiento genético correspondiente.

Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease?

We report a case of amyloidosis in association with hyperimmunoglobulinemia D syndrome (HIDS). The patient showed typical clinical features of HIDS. He had crescentic glomerulonephritis progressing to end-stage renal disease at age 13 years. Eight years later, he developed an AA-type amyloidosis with extensive involvement of the intestine, respiratory tract, and thyroid gland. These unusual complications of HIDS seriously challenge the assumption that the disease is associated with a good prognosis.

The systemic autoinflammatory diseases: inborn errors of the innate immune system.

The autoinflammatory syndromes are a newly recognized group of immune disorders that lack the high titers of self-reactive antibodies and T cells characteristic of classic autoimmune disease. Nevertheless, patients with these illnesses experience unprovoked inflammatory disease in the absence of underlying infection. Here we discuss recent advances in eight Mendelian autoinflammatory diseases. The causative genes and the proteins they encode play a critical role in the regulation of innate immunity. Both pyrin and cryopyrin, the proteins mutated in familial Mediterranean fever and the cryopyrinopathies, respectively, are involved in regulation of the proinflammatory cytokine, IL-1beta, and may influence the activity of the transcription factor, NFkappaB. NOD2, the Blau syndrome protein, shares certain domains with cryopyrin and appears to be a sensor of intracellular bacteria. PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses. Somewhat unexpectedly, mutations in the p55 TNF receptor lead not to immunodeficiency but to dramatic inflammatory disease, the mechanisms of which are still under investigation. Finally, the discovery of the genetic basis of the hyperimmunoglobulinemia D with periodic fever syndrome has provided a fascinating but incompletely understood link between cholesterol biosynthesis and autoinflammation. In this manuscript, we summarize the current state of the art with regard to the diagnosis, pathogenesis, and treatment of these inborn errors of the innate immune system.

[Familial Mediterranean fever among the autoimmune diseases]. / La maladie périodique au sein des maladies auto-inflammatoires.

During the first attacks of familial Mediterranean fever, each of the disease symptoms can suggest a series of disorders. When the disease is older, the recurrence of symptoms may simulate some systemic diseases, but mainly suggests familial Mediterranean fever, one of a group of hereditary autoinflammatory diseases. Before the gene for familial Mediterranean fever was identified, various sets of criteria were used for diagnosis. The presence of MEFV mutations confirms the diagnosis, but the clinical criteria still determine who should undergo this genetic testing. The genotype-phenotype correlations add a prognostic dimension to the mutations identified. Genotyping can also lead to the diagnosis of the other autoinflammatory diseases, which constitute the basis of the differential diagnosis of familial Mediterranean fever. The hyperimmunoglobulinemia D syndrome (HIDS) is very similar to familial Mediterranean fever in its recessive transmission and abdominal and articular symptoms. It can be distinguished by the European origin of the patients, the presence of cervical lymph nodes and the increased IgD levels. Of the diseases with dominant transmission, the TNF receptor-associated periodic syndromes (TRAPS) are suggested by periorbital edema and migrating inflammatory cellulitis. Muckle and Wells syndrome is revealed by episodes of fever with urticaria and arthralgia, complicated by deafness and amyloidosis. Mutations in the same gene are responsible for two disorders, both appearing in childhood: familial cold urticaria syndrome (FCUS) and chronic infantile neurocutaneous articular syndrome (CINC). The pathogenesis of familial Mediterranean fever is still unclear. Pyrin/marenostrin, the protein produced by the MEFV gene, appears to hae a physiological antiinflammatory effect that inhibits proinflammatory cytokines. Mutation of the gene may eliminate this feedback mechanism and expose the patient to flares from any inflammatory stimulus, even minimal. Amyloid is produced by the serum amyloid A protein (SAA), and its occurrence is influenced by the type of MEFV mutation, but also the genotype of the gene producing SAA.