A Randomized, Double-Blind, Placebo-Controlled Phase III Trial On The Efficacy and Safety of Tocilizumab in Patients With Colchicine-Resistant or -Intolerant Familial Mediterranean Fever

Objective To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in patients with familial Mediterranean fever (FMF). Methods We performed a double-blind, randomized, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study. Results We randomly assigned 23 patients to either TCZ (n = 11) or placebo (n = 12). The TCZ–placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189–2.531; P = 0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240–0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups. Conclusion Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.

The Assessment of Selected miRNA Profile in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is the most prevalent autoinflammatory disease. Typical findings are recurrent fever attacks with serositis, skin rash, and synovitis. FMF is caused by mutations in the MEFV gene, encoding pyrin protein. Pyrin functions in innate immunity and triggers inflammation via inflammatory mediators’ production and acts as the primary regulatory component of the inflammasome. On the other hand, various miRNAs play crucial roles in the pathogenesis of different types of cancers and immune-related and neurodegenerative diseases. However, their association with FMF is still unclear. Therefore, in this study, we assessed the roles of selected thirteen miRNAs associated with immune functions. We recruited genetically diagnosed 28 FMF patients and 28 healthy individuals. The expression profiling of the miRNAs was determined by qRT-PCR and normalized to SNORD61. Our analysis revealed that miR-34a-5p, miR-142-3p, miR-216a-5p, miR-340-5p, miR-429, and miR-582-5p were upregulated, whereas miR-107, miR-569, and miR-1304-5p were downregulated in the FMF patients. Among them, miR-107 was found to be the most remarkable in M694V homozygous mutants compared to other homozygous mutants. During clinical follow-up of the patients with M694V mutation, which is closely related to amyloidosis, evaluation of mir-107 expression might be crucial and suggestive. Our results showed that miRNAs might serve a function in the pathogenesis of FMF. Further studies may provide novel and effective diagnostic and therapeutic agents that target examined miRNAs. Targeting miRNAs in FMF seems to be promising and may yield a new generation of rational therapeutics and diagnostic or monitoring tools enabling FMF treatment.

Description and Analysis of a Novel Subtype of the Anti-Synthetase Syndrome Characterized by Frequent Attacks of Fever and Systemic Inflammation in a Single-Center Cohort Study

ObjectivesThe aim of this study was to investigate anti-synthetase syndrome (ASyS) patients who presented with recurrent episodes of fever and systemic inflammation.MethodsA retrospective cohort of Chinese ASyS patients (n=126) in our center (between January 2013 and January 2020) was included. Patients presenting with concomitant autoimmune rheumatic diseases or malignancies were subsequently excluded. The number of non-infectious fever attacks and attack frequency were recorded and calculated. Patients with two or more attacks and within the upper three quartiles of attack frequency were defined as high-inflammation group. Univariate and multivariate analyses were carried out to characterize the high-inflammation subtype.ResultsOut of 113 eligible patients with an average of 5 years follow up, 25 patients were defined as the high-inflammation group (16 for anti-Jo1, 9 for anti-PL7), with an average of 1.12 attack/patient-year. Compared to low-inflammation group (0–1 attack only and a frequency lower than 0.5 attack/patient-year), the high-inflammation group had higher occurrence of fever and rapid progressive interstitial lung disease (RPILD) as the first presentation (84% vs. 21% and 40% vs. 9%, respectively, both p<0.01). Anti-PL-7 was related to the more inflammatory phenotype (p=0.014). Cumulative disease-modifying agent exposures (>=3) were much higher in the high-inflammation group (60% vs. 26%), while biological agents, i.e., rituximab and tocilizumab, showed better “drug survival” for Jo-1+ and PL-7+ ASyS patients with high inflammation, respectively, in our cohort.ConclusionsASyS with recurrent systemic inflammatory episodes reflects a subtype of more aggressive and refractory disease in the spectrum of ASyS. Increased awareness of this subtype might lead to more appropriate management.

The use of an interleukin 1 inhibitor in a patient with atypical course of periodic fever

The article presents a case of periodic fever (PF) in a 35-year-old patient, who did not have hereditary and proven genetic factors of the disease, which was characterized by an atypical course with variable in duration and frequency severe abdominal pain and febrile fever attacks, increased acute phase reactants and ineffectiveness of colchicine intake. Differential diagnosis with a wide range of febrile conditions was performed. Daily subcutaneous therapy of interleukin 1 inhibitor (iIL1) at a dose of 100 mg was used as a diagnostic marker to confirm the diagnosis of PF. As a result of the therapy, a rapid (within a few hours after injection) relief of the current attack of the disease, normalization of serum CRP levels, and further complete control over the disease (no relapses) were achieved. Our observation shows that a positive response to iIL1 therapy can serve as a diagnostic marker of PF.

AB0988 CLINICAL FEATURES AND ANALYSIS OF MEFV GENE IN 31 PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF)

Background:FMF is recessive systemic autoinflammatory disorder characterized by recurrent fever, peritonitis, pleuritis, pericarditis and arthritis accompanied with headache and abdominal pain. Mutation of MEFV gene encoding pyrin resulted in inflammasome activation and the uncontrolled production of IL-1β. Overview of pathogenesis, clinical features and management in Japanese patients with FMF had been reported. However, the differences of clinical features between mutated and non-mutated of MEFV still remain unclear.Objectives:We have analyzed 31 Japanese patients with FMF in Gifu district to clarify the association between various clinical features and mutation ofMEFV.Methods:Genomic DNA were purified from white blood cells in 31 FMF patients, and mutated MEFV has been explored. We have analyzedMEFV, TNFRSF1A, MVK and NLRP3 genesin 31 patients with FMF except for 1 patient. Therefore, we excluded another autoinflammatory diseases such as TNF receptor-associated syndrome (TRAPS), mevalonate kinase deficiency and cryopyrin-associated periodic syndrome. Clinical symptoms and laboratory data were analyzed around onset time. Each patient had been treated with colchicine (0.5-2 mg).Results:Characteristics of Patients with FMF (22 female/9 male) were as follows; Onset time were 0-56 years-old (21.4 ±11.8), and Frequencies of clinical symptoms such as periodic fever, headache, abdominal pain, arthralgia, chest pain, cervical lymph nodes swelling, and myalgia were 31/31, 9/31, 8/31, 6/31, 5/31, 3/31 and 1/31, respectively (double symptoms were observed). Patients with FMF were divided into 3 groups as follows; Patients with typical compound heterozygous mutations of MEFV (E148Q /M694I) which indicated exon 10 mutation, were 5 cases (G1). Patients with atypical mutations, except for exon 10, such as 133G>A in 3UTR, exon 1 (E84K), 2 (L110P, E148Q), 3(R202Q, P257L, G304R, P369S, R408Q), 5(S503C) and 9(I591M) were 13 cases (G2). Patients with no mutations in MEFV gene were 12 cases (G3). There were no significant differences of age at first visiting hospital (FV)and onset age of fever attack (O) (FV: 29.0 ± 15.6, 27.1 ± 12.5 years-old (yo) and 34.7 ± 12.7 yo, O: 21.0 ± 17.6 yo, 17.8 ± 12.1 yo and 25.2 ± 6.5). But significant differences in duration of fever attack (D) and frequency of fever attack (FF) between G1 and G2 or G3 were observed as follows; (D: 2.2 ± 0.4 days vs 5.5 ± 3.1 days, P<0.05, and 3.8 ± 1.7 days), FF: 0.72 ± 0.3/month (M), 1.24 ± 1.1/M, and 1.5 ± 0.7/M vs group1, P<0.05), respectively. Laboratory examinations such as WBC, CRP and serum amyloid A (SAA)at fever attack were not significantly different between 3 groups. All of those patients were effective for colchicine treatment except for 2 patients in group 1 because of loss of hair, severe diarrhea and liver dysfunction due to side effects of colchicine. Finally, 4 patients in G1and G2 received canakinumab treatment. Patients withMEFVmutations have no family histories. Mutations of E148Q were found in 12 patients (40%).Conclusion:We have examined association between clinical features and mutations of MEFV in 31 patients in Gifu district, suggesting that duration of fever attacks and frequency of fever attacks in G1 are significantly shorter than G2 and G3, respectively in Japanese patients with FMF. Mutations of E148Q in exon 2 were observed in 16-23 % of normal Japanese patients, indicating that E148Q is the polymorphism or accelerating factor.Disclosure of Interests:None declared

Pengaruh pemberian minyak ikan terhadap konsentrasi asam lemak dan gejala klinis malaria

The aim of the study is to find out the effects of fish oil supplementation on fatty acids concentration (Eicosapentanoat Acid and Docosahexaenoat Acid), fever attacks and Dikke Drupple (DDR) interpretation of samples. This study was designed as “A Randomized Double Blind Pretest and Post-test Controled Group“. Samples were divided into two groups, experiment group with fish oil suplementation (8% EPA, 35 DHA) and control group (placebo) for 8 weeks. This study was conducted in a malaria endemic, Kadaila village, subdistrict of Karossa, District of Mamuju in 2003. The result of the study showed significant increased concentration of EPA and DHA of the experiment group than the control group (p 0,05). The fever attack was significantly decreased (p 0,05) in experiment group than the control group, while DDR was not significantly different (p 0,05) between two groups.

G0018212_USWATUN INSANI M

Every parent would want their children to grow healthy. Parents will feel very worried when a child has an illness. This is natural because children have an imperfect immune system. So that children are more susceptible to disease than adults. One of the most common symptoms of a child is fever. Fever is the body's response to an infection. This situation becomes dangerous when a fever attacks a baby, because his immune system has not been able to fight the pathogen. However, not all fever is dangerous. There are a number of conditions that must be addressed immediately. Handling and managing fever caused by viruses is different from those caused by bacteria. Therefore, a doctor must understand correctly about the causes of fever to diagnose a disease, provide management quickly, and educate the family in order to prevent more severe conditions