A clinical case of Crohn's disease with late-onset familial Mediterranean fever

Recurrent AA Amyloidosis in a Kidney Transplant

The etiology and pathogenesis of recurrent hereditary polyserositis (RHP) remain undetermined. There is a good evidence for a genetic basis (transmission being by a recessive Mendelian mode of inheritance), but not all cases have a family history and an infective (or other environmental) components has not been excluded. The marked variation in presentation and complications (in particular the prevalence of amyloid deposition) in different series suggests that this might not be a homogeneous entity. Vascular involvement is a basic prerequisite for the periodic attacks, and evidence for transient immunological abnormalities is incontrovertible. There are no reliable diagnostic techniques. Colchicine is of value in treatment, but its mode of action is unclear. More macro- and microepidemiological studies are required and will be of paramount importance. Clinical observations and molecular genetic studies should address the possibility that two or more immunological or metabolic defects might be interwoven; why for example do only some affected groups develop AA amyloidosis? Simple, non-invasive diagnostic tests are required for the uncomplicated disease and also for the presence of amyloid deposition. Preventive strategies might eventually involve genetic engineering techniques, but in the immediate future, education of doctors and other health care workers - to raise the "index of awareness" of RHP, in order that colchicine treatment can be commenced early in the disease - forms an important strategy. Colchicine therapy is not without complications and an alternative chemotherapeutic agent should be sought.

Background Familial Mediterranean fever (FMF) is an autosomal recessively inherited autoinflammatory disease and begins in childhood. In nearly 60% of patients, the first attack occurs before the age of 10, and in 90% of them before the age of 20 years. There isn’t a prospective study designed for comparing childhood onset and adult onset FMF. Objectives To compare the demographic data, clinical features, genetic analysis, laboratory values and severity scores of both childhood and adult onset FMF. Compliance and resistance to colchicine, presence of accompanying diseases and complications due to FMF were also analyzed and reviewed. Methods The patients were divided into two groups; group I: children with FMF (symptoms begin before 18 years of age) and group II: adults with FMF (symptoms begin after 18 years of age). A questionnaire for collecting age at disease onset, sex, age at diagnosis, delay at diagnosis and duration of the disease, family history of FMF, consanguinity and accompanying diseases were filled. The questions were asked by an adult and pediatric rheumatologist to both groups by face to face interviews. Genetic analysis results and treatment protocols were taken from patient’s charts. Laboratory data concerning complete blood count, ratio of urine protein to creatinine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) levels were obtained during their routine follow-up at attack-free period. Results There were 178 (60.3%) children with the diagnosis of FMF; 73 female and 104 male and 117 (39.7%) adults diagnosed as FMF after 18 years of age; 69 female and 48 male. The mean±SD age at symptom onset, at the diagnosis and current age was 4.92±3.03, 6.45±3.61, 11.59±4.38 for group I and was 18.35±10.34, 32.23±11.62, 38±11.64 for group II, respectively. Consanguinity was significantly more frequent among children with FMF (36.1%). A positive family history of FMF was similarly present in 102 (57.6%) of group I and 66 (56.4%) of group II. Twelve (10.2%) adult patient have FMF at their children. Family history of amyloidosis was equally distributed between groups; 6.2% in group I and 6.8% in group II. The median number of FMF attacks per year was 18 in children and 15 in adults. While children were having significantly more frequent attacks, the duration of attacks were longer in adults compared to children (p Conclusion Both clinical features and acute phase response in FMF were less pronounced in patients diagnosed at adulthood. Children were having more frequent attacks,but accompanying diseases were more common in adults. While following patients taking age of the patient in to account will help to better understand the disease course. Reference [1] Yasar Bilge NS, Sari I, Solmaz D, et al. Comparison of early versus late onset familial Mediterranean fever. Int J Rheum Dis. 2018 Apr;21(4):880-884. doi: 10.1111/1756-185X.13259. Epub 2018 Jan 5. Acknowledgement None Disclosure of Interests None declared

BackgroundOur previous nation-wide survey showed the clinical manifestations and prevalence of Japanese Familial Mediterranean Fever (FMF) patients. However, the clinical differences between young-onset FMF (YOFMF), adult-onset FMF (AOFMF), and late-onset...

An 86-year-old Caucasian man had prior episodes of fever (up to 38°C), mild abdominal pain, tachycardia, and malaise in the last 3months, lasting 2-3days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. KEY POINTS: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.

The goal of this study was to evaluate the impact of coexisting familial Mediterranean fever (FMF) on Crohn's disease (CD) patients' phenotype and disease course in an endemic region for FMF. CD and FMF are inflammatory diseases characterized by recurrent abdominal pain and fever attacks. The impact of coexisting FMF on CD patients' phenotype and disease course is currently unknown. We reviewed the medical records of 210 adult CD patients who were regularly followed up at a tertiary gastroenterology clinic between November 2006 and April 2018. The patients were divided into FMF positive (CD-FMF) and FMF negative (CD-control) groups. The severity of CD was assessed by the rate of hospitalization because of CD, the need for biological therapy, and whether surgery was performed for CD. Eight (3.8%) of 210 CD patients have concomitant FMF, which is 35 to 40 times higher than expected in an endemic region for FMF. Baseline demographic parameters, location/behavior of the CD, and initial therapeutic regimens were similar between the 2 groups. The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04). A significantly greater proportion of the CD-FMF patients had received biological therapy (50% vs. 11.9%; P =0.012). Steroid dependence and CD-related hospitalization rates in the CD-FMF group were relatively higher but were not statistically significant (37.5% vs. 15.3 and 62.5% vs. 41.1%). Our findings indicate that the disease course of CD tends to be more severe in patients with coexisting FMF.

Purpose: A 22-year-old woman with familial Mediterranean fever (FMF) treated with colchicine and a strong family history of Crohn's disease presented with severe lower abdominal pain, nausea, vomiting and fevers up to 104 F. The differential diagnosis for her symptoms included Crohn's, ulcerative colitis, appendicitis, intussusception, cholecystitis, pelvic inflammatory disease, peptic ulcer and colchicinerefractory FMF flare. Physical exam was unremarkable, except for abdominal tenderness predominantly in the RLQ with modest guarding. Laboratory evaluation showed normal electrolytes, CBC, amylase/lipase, TFTs, PTH and vitamin levels. Stool and urine cultures were negative. Gynecologic evaluation, including transvaginal ultrasound, was normal. MRE showed no evidence of bowel wall inflammation or obstruction. Upper endoscopy biopsies showed a chronic chemical gastropathy with no Barrett's, no H. pylori, and normal jejunal villous architecture. Colonoscopy was normal, with normal terminal ileum and colonic mucosal biopsies. Given the recurrence of symptoms and greater than one febrile attack per month, the patient was deemed to have colchicine-resistant FMF and was referred to rheumatology for initiation of anti-IL1β biologic therapy. Discussion: FMF is a hereditary auto-inflammatory disease characterized by periodic fevers and serositis triggered by deregulated inflammasome production of IL-1β. With peritonitis, abdominal pain and fever being the most common manifestations, gastroenterologists need to consider FMF in the DDX of IBD-associated inflammatory symptoms. FMF is caused by mutations in the MEFV gene encoding pyrin. Mutant pyrin fails to regulate caspase-1 activity and additionally activates NFκB. Careful follow-up of FMF patients is critical as they are at increased risk of developing late-onset IBD. This increased risk for IBD may be related to the close association of the CD-susceptibility gene NOD2 with the MEFV gene on chromosome 16. Pyrin also interacts with the innate immune intracellular NOD-like receptor Nlrp3, which has been shown to contribute to Crohn's susceptibility. Nlrp3 is a crucial regulator of intestinal homeostasis, mediating assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Although colchicine is the first line of treatment for FMF, case reports have shown some efficacy with anti-TNF biologics. However, IL-1β biologics are emerging as the best second-line therapy for colchicine-resistant FMF patients. Despite the FMF and IBD overlap in inflammasome deregulation of the IL-1β pathway, studies are lacking on the effectiveness of colchicine or anti-IL-1β therapy for IBD.

Therapy of autoinflammatory syndromes

BackgroundFamilial Mediterranean Fever (FMF), an autoinflammatory disease, is characterized by self-limited inflammatory attacks of fever and polyserositis along with high acute phase response. Although colchicine remains the mainstay in treatment, intolerance and resistance in a certain portion of patients have been posing a problem for physicians.Main bodyLike many autoimmune and autoinflammatory diseases, many colchicine-resistant or intolerant FMF cases have been successfully treated with biologics. In addition, many studies have tested the efficacy of biologics in treating FMF manifestations.ConclusionSince carriers of FMF show significantly elevated levels of serum TNF alpha, IL-1, and IL-6, FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination with biologics.

Background:Retinol binding protein 4 (RBP4) is a plasma retinol transporter that transports retinol from liver to periphery. RBP4 has been studied as a biomarker in metabolic and neoplastic conditions, however its association with inflammation is not clear. Serum amyloid A (SAA), another retinol binding protein, has been known as a sensitive biomarker of inflammation in familial Mediterranean fever (FMF) and other autoinflammatory disorders. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and SAA are commonly used as acute phase reactants, but they are not successful in differentiating non-infectious inflammatory conditions from infections.Objectives:We aimed to evaluate the potential of serum RBP4 as a biomarker of acute phase response and to determine its performance in differentiation of inflammation of patients with FMF and AA amyloidosis from infections.Methods:A total of 169 participants in 5 groups, consisting of FMF (n = 60), FMF with AA amyloidosis (n = 58), non-FMF AA amyloidosis (n = 23), infections (n = 10, 3 pneumonia, 3 sepsis, 1 pyelonephritis, 1 fungal infection, 1 cellulitis, 1 disseminated zoster), and healthy controls (HC) (n = 18), were included and evaluated cross sectionally. Hemogram and serum CRP, ESR, SAA, ferritin, creatinine, AST, ALT, albumin levels were recorded from the patient charts. FMF and FMF + amyloidosis patients were evaluated during attack-free period. Serum RBP4 levels were investigated by ELISA (Elabscience, USA). Mean values and relative changes compared to healthy controls were evaluated for SAA, CRP, RBP4 levels in all groups.Results:Serum RBP4 level was found to be higher in FMF group compared to the patients with infection (p = 0.002) and HC (p <0.001) as well as in patients with amyloidosis. Compared to HC, 47%, 28% and 27% increase was observed in mean RBP4 levels in FMF, FMF + amyloidosis and non-FMF amyloidosis patients, despite no significant change in patients with infections. However, CRP and SAA elevations were much more prominent in patients with infections (58 and 134 times, respectively) compared to the patients with FMF (13 and 35 times, respectively), FMF + amyloidosis and non-FMF amyloidosis (Table 1). There was no significant difference in RBP4 levels between FMF, FMF-amyloidosis and non-FMF amyloidosis groups. CRP, ESR, ferritin and SAA levels were higher in the infection group compared to HCs.Table 1.Demographic features and laboratory findings of the participantsVariablesFMF(n=60)FMF- Amyloidosis(n=58)Non-FMF-AA Amyloidosis(n=23)Infection(n=10)Healthy control(n=18)Female/Male46/1433/258/153/78/10Age (SD)*38±13(18-74)43±11(21-69)53±1365±1533±9Creatinine (mg/dL)*0,8±0,21,7±1,72,0±1,61,7±1,00,7±0,2Albumin(mg/dL)*4,7±0,44,3±0,63,3±0,93,0±0,94,8±0,2Ferritin (ng/mL)*70±94245±315139±168554±3883±72RBP4 (ng/mL)*772±183671±214666±256512±204524±117RBP4 (median)770(434-1142)653(227-1259)645(331-1214)487(226-876)498(566-738)CRP (mg/L)*16±47,112,8±32,825,7±36,469±36,81,2±1,2SAA (mg/dL)*10,3±31,45,0±13,97,1±14,140,2±18,50,3±0,1ESR*15±1319±1641±2945±427±5Relative RBP4 increase1,47±0,351,28±0,411,27±0,490,98±0,39Relative CRP increase13,4±39,210,6±27,321,4±30,357,7±30,6Relative SAA increase34,5±104,816,0±45,723,7±47,1133,9±61,7*mean, RBP4 (Retinol Binding Protein 4), C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), Serum Amyloid A (SAA).Conclusion:This preliminary study showed that RBP4 levels may be increased about 1.5 times in FMF and to lesser extent in AA amyloidosis patients despite no significant change during acute phase response of different infections. Patients with infections show strong CRP and SAA response, and the differential response of RBP4 in FMF patients warrants further analysis in larger group of patients with different clinical characteristics.Disclosure of Interests:None declared

Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis.

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease. One of the common characteristics of this disease is its young age predominance. Nearly 90% of patients experience disease flares during early adult age periods. Currently there are limited data for the comparison of early versus late onset FMF and therefore the primary aim of this study was to investigate these two subsets with regard to their certain demographic, clinical and genetic differences. Early (≤20years, Group 1) and late (>20years, Group 2) onset FMF patients were identified from the national FMF registry that involves 2246 patients from 15 adult rheumatology clinics located in different geographical areas of Turkey. Of the 2246 patients, 1633 (72.7%) were aged ≤20years old (Group 1) and the remaining 613 were older than 20years (Group 2). Delay in diagnosis was longer in Group 1 and fever, peritonitis, pleuritis, erysipelas-like erythema (ELE), arthritis, family history of FMF and amyloidosis were more common in Group 1. On the other hand, sex distribution, rates of amyloidosis, vasculitis and kidney failure were not different between the groups. Among patients with available genotypes, homozygous and heterozygous M694V mutations weresignificantly higher and heterozygous E148Q mutation was significantly lower in Group 1 compared to Group 2. Patients with FMF whose symptoms start before 20years of age seem to have severe symptoms and M694V mutation may be responsible for the early expression of the disease.

Familial Mediterranean Fever (FMF), the most common form of the hereditary autoinflammatory disorders, is characterized by recurrent attacks of fever along with serosal or synovial inflammation lasting usually 12 to 72 hours. FMF is associated with impaired functional ability, and the persistent disabling features and chronic pain, emotional and physical limitations can have a negative impact on the health-related quality of life (QoL) of the patients. There is no established treatment available for those resistant or intolerant to standard of care colchicine treatment. Interleukin-1 (IL-1) plays a pivotal role in the pathogenesis of crFMF. Canakinumab, a fully human, selective, anti-IL-1β monoclonal antibody, binds to IL-1β and inactivates its signalling activity. Gul et al. have described the efficacy and safety of canakinumab in adults with colchicine resistant (cr) FMF in a local pivotal phase II trial. Here, we report the effect of canakinumab treatment on QoL measured by SF-36 Questionnaire.

Background: To investigate the clinical features of Japanese patients with Familial Mediterranean Fever (FMF), we evaluated the frequency of attacks, treatment responses, and adverse effects in 27 patients with FMF treated with colchicine or canakinumab in a real-world clinical setting. Methods: We retrospectively reviewed 27 Japanese patients with FMF treated at our institute between April 2012 and June 2023. All patients were diagnosed with FMF according to the Tel-Hashomer criteria. We performed genetic analyses of the MEFV gene using targeted next-generation sequencing. The clinical response was monitored through the number of attacks, and inflammatory markers were monitored through the C-reactive protein (CRP), and serum amyloid A (SAA) concentrations. Colchicine resistance was defined as the presence of at least one attack/month despite administration of the maximum tolerated dose of colchicine for at least 6 months, and C-reactive protein and serum amyloid A levels above the normal range between attacks. Results: A total of 27 patients diagnosed with FMF were enrolled in this study and the median follow-up period was 36.4 months. The median attack frequency was 1.0 (interquartile range: 0.33–1.0) every 3 months before treatment initiation. All the patients (n = 27) were treated with colchicine. Among the 27 patients, 20 (71.8%) showed a clinical response and 7 (25.9%) showed an incomplete response with sufficient doses of colchicine (n = 5) and non-sufficient doses (n = 2). Two patients on non-sufficient doses were unable to increase colchicine to the maximum dose due to diarrhea and liver dysfunction. All seven patients achieved a reduction in attack frequency after the initiation of canakinumab. No serious adverse events associated with canakinumab treatment were observed. In these seven patients with colchicine-resistant FMF (crFMF), the MEFV exon 10 variant was not detected, and the absence ratio of the MEFV variant was significantly higher compared to those without crFMF. Conclusions: Colchicine was effective in 71.8% (20/27) of Japanese patients with FMF; however, the remaining patients (7/27) had crFMF. Canakinumab effectively controlled febrile attacks in crFMF, even in the absence of pathogenic MEFV exon 10 variants.

Objectives: Most patients with familial Mediterranean fever (FMF) have their first attack at age < 20 years. Information about late-onset (age ≥40 years) FMF is limited. We aimed to evaluate the demographic, clinical, and genetic characteristics of late-onset FMF patients in the Japanese population.Methods: We retrospectively analyzed 292 patients with FMF. Patients were divided into three groups according to age of disease onset: Group I, ≤19 years; Group II, 20–39 years; and Group III, ≥40 years.Results: Of 292 patients, 44 (15.1%) experienced their first attack at age ≥40 years. While high fever (97.7%) and arthritis (45.5%) were common symptoms in Group III patients, peritonitis (40.9%) and pleuritis (25.0%) were significantly lower than in other groups. The frequency of patients carrying p.M694I (18.2%), which is the most representative mutation in Japan, was significantly lower in Group III than in Group I. The response to colchicine therapy was good (95.1%) and similar in all groups.Conclusions: In Japan, more patients than expected had late-onset FMF. They had a milder form of disease, with less frequent peritonitis and pleuritis. The response to colchicine treatment was good. Clinicians should consider FMF for patients with unexplained recurrent febrile episodes, regardless of age.