Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia. Thus far, however there have been no reports of CAPS in Korea. Herein, we report 3 cases of CAPS for the first time in Korea. The first case, a 28-year-old man with recurrent urticaria, arthralgia and fever induced by cold, all of which were observed in his father, showed elevated erythrocyte sedimentation rate and C-reactive protein. He exhibited a p.Gly303Asp variant of the NLPR3 gene. The second case, a 2-year-old girl who had recurrent urticaria, arthritis and oral and genital ulcers, was positive for HLA B51 and a p.Glu569Lys mutation in exon 3 of the NLRP3 gene. Administration of anakinra greatly improved her symptoms. The third case, a 4-year-old boy who presented with recurrent urticaria, arthralgia, and fever, exhibited a p.Val72Met mutation in exon 1 of the NLRP3 gene. Administration of tocilizumab improved all of his symptoms. This small case series suggests that clinicians consider CAPS and conduct genetic studies when arthralgia and fever are accompanied by urticaria in Korea.
Adult ; Arthralgia ; Arthritis ; Blood Sedimentation ; C-Reactive Protein ; Child, Preschool ; Cryopyrin-Associated Periodic Syndromes ; Exons ; Fathers ; Fatigue ; Female ; Fever ; Humans ; Interleukin 1 Receptor Antagonist Protein ; Korea ; Male ; Ulcer ; Urticaria

PURPOSE: The aim of this study was to evaluate the clinical characteristics of children diagnosed as cryopyrin-associated periodic syndrome (CAPS) in Korea. METHODS: Diagnosis was made based on clinical features and confirmed by a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene. Especially, osteocartilaginous overgrowth in the patella or distal femur was so characteristic that its presence warranted a diagnosis of chronic infantile neurologic cutaneous and articular/NOMID. RESULTS: We observed the clinical features of 9 Korean CAPS patients. All the patients suffered from an urticarial rash with recurrent fever. Among the 9 patients, 6 presented with rash and 4 with fever on the 1st or 2nd days of birth. Eight patients showed myalgia, and 7 patients showed arthralgia in the joints, and 6 patients showed radiologic findings of arthropathy including cupping of the metaphysis, excessive growth of the epiphysis, osteopenia or overgrowth of the cartilage. Four patients showed brain atrophy, enlarged ventricles or leptomeningeal enhancement on magnetic resonance imaging. Intellectual disability was observed in 1 patient. Five patients had eye involvement as conjunctivitis, uveitis, chorioretinitis, avascular area or papillary edema, and 3 patients showed progressive hearing loss. All 9 patients showed increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). CONCLUSIONS: All the patients carried a mutation on exon 3 of the CIAS1 gene. After the anakinra (interleukin-1 receptor antagonist) therapy, the fever and rash immediately disappeared, and CRP and ESR were improved.
Arthralgia ; Atrophy ; Blood Sedimentation ; Bone Diseases, Metabolic ; Brain ; C-Reactive Protein ; Cartilage ; Child ; Chorioretinitis ; Conjunctivitis ; Cryopyrin-Associated Periodic Syndromes ; Diagnosis ; Edema ; Epiphyses ; Exanthema ; Exons ; Femur ; Fever ; Hearing Loss ; Humans ; Intellectual Disability ; Interleukin 1 Receptor Antagonist Protein ; Joints ; Korea ; Magnetic Resonance Imaging ; Myalgia ; Parturition ; Patella ; Uveitis

Chronic urticaria may often be associated with interleukin (IL)-1-mediated autoinflammatory disease, which should be suspected if systemic inflammation signs are present. Here, we report a case of Schnitzler's syndrome without monoclonal gammopathy treated successfully with the IL-1 receptor antagonist anakinra. A 69-year-old man suffered from a pruritic urticarial rash for 12 years. It became aggravated episodically and was accompanied by high fever, arthralgia, leukocytosis, and an elevated C-reactive protein and erythrocyte sedimentation rate. The episodes each lasted for over one week. Neutrophilic and eosinophilic inflammation was found on skin biopsy. However, serum and urine electrophoresis showed no evidence of monoclonal gammopathy. The cutaneous lesions were unresponsive to various kinds of anti-histamines, systemic glucocorticoids, colchicine, cyclosporine, dapsone, and methotrexate, which were administered over a span of 3 years immediately preceding successful treatment. A dramatic response, however, was observed after a daily administration of anakinra. This observation suggests that the correct diagnosis of this case is Schnitzler's syndrome without monoclonal gammopathy. For an adult patient with refractory chronic urticaria and systemic inflammation, Schnitzler's syndrome could be considered as a possible differential diagnosis. Although the typical form of Schnitzler's syndrome exhibits the presence of monoclonal gammopathy as a diagnostic criterion, monoclonal gammopathy may be absent in an atypical form. In such a situation, an IL-1 antagonist should be effective for the management of chronic urticaria.
Aged ; Blood Sedimentation ; C-Reactive Protein/metabolism ; Chronic Disease ; Humans ; Interleukin 1 Receptor Antagonist Protein/therapeutic use ; Leukocytes/metabolism ; Male ; Paraproteinemias/complications ; Schnitzler Syndrome/blood ; Schnitzler Syndrome/drug therapy ; Urticaria/complications

The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of interleukin-1β and tumor necrosis factor-α at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.
Administration, Intranasal* ; Animals ; Blood-Brain Barrier ; Brain ; Brain Ischemia* ; Cytokines ; Humans ; Infarction, Middle Cerebral Artery ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1* ; Ischemic Attack, Transient ; Male ; Methods ; Microglia ; Models, Animal* ; Necrosis ; Neurons ; Neuroprotection ; Rats* ; Rats, Sprague-Dawley ; Stroke

OBJECTIVETo explore the effect of colon cancer cell-derived interleukin-1α on the migration and proliferation of human umbilical vein endothelial cells as well as the role of IL-1α and IL-1ra in the angiogenesis process.

METHODSWestern blot was used to detect the expression of IL-1α and IL-1R1 protein in the colon cancer cell lines with different liver metastatic potential. We also examined how IL-1α and IL-1ra influence the proliferation and migration of umbilical vascular endothelial cells assessed by PreMix WST-1 assay and migration assay, respectively. Double layer culture technique was used to detect the effect of IL-1α on the proliferation and migration of vascular endothelial cells and the effect of IL-1ra on the vascular endothelial cells.

RESULTSWestern blot analysis showed that IL-1α protein was only detected in highly metastatic colon cancer HT-29 and WiDr cells, but not in the lowly metastatic CaCo-2 and CoLo320 cells.Migration assay showed that there were significant differences in the number of penetrated cells between the control (17.9±3.6) and 1 ng/ml rIL-1α group (23.2±4.2), 10 ng/ml rIL-1α group (31.7±4.5), and 100 ng/ml rIL-1α group (38.6±4.9), showing that it was positively correlated with the increasing concentration of rIL-1α (P<0.01 for all). The proliferation assay showed that the absorbance values were 1.37±0.18 in the control group, and 1.79±0.14 in the 1 ng/ml rIL-1α group, 2.14±0.17 in the 10 ng/ml rIL-1α group, and 2.21±0.23 in the 100 ng/ml rIL-1α group, showing a positive correlation with the increasing concentration of rIL-1α(P<0.01 for all). IL-1ra significantly inhibited the proliferation and migration of vascular endothelial cells (P<0.01). The levels of VEGF protein were (1.697±0.072) ng/ml, (3.507±0.064)ng/ml and (4.139±0.039)ng/ml in the control, HUVECs+ IL-1α and HUVECs+ HT-29 co-culture system groups, respectively, showing a significant difference between the control and HUVECs+ 10 pg/ml rIL-1α groups and between the control and HUVECs+ HT-29 groups (P<0.01 for both).

CONCLUSIONSOur findings indicate that colon cancer cell-derived IL-1α plays an important role in the liver metastasis of colon cancer through increased VEGF level of the colon cancer cells and enhanced vascular endothelial cells proliferation, migration and angiogenesis, while IL-1ra can suppress the effect of IL-1α and inhibit the angiogenesis in colon cancer.

Blotting, Western ; Caco-2 Cells ; Cell Line, Tumor ; Cell Movement ; physiology ; Cell Proliferation ; physiology ; Coculture Techniques ; Colonic Neoplasms ; blood supply ; metabolism ; pathology ; Human Umbilical Vein Endothelial Cells ; cytology ; Humans ; Interleukin 1 Receptor Antagonist Protein ; metabolism ; physiology ; Interleukin-1alpha ; metabolism ; physiology ; Liver Neoplasms ; secondary ; Neovascularization, Pathologic ; etiology

OBJECTIVETo observe the therapeutic effects of continuous plasma filtration absorption (CPFA) treatment on burn sepsis.

METHODSThirty burn patients with sepsis hospitalized in Beijing Fengtai You'anmen Hospital from July 2009 to October 2012 were treated by CPFA for twice besides routine treatment. The blood samples were collected at five sites (A, B, C, D, and E, respectively) of blood purification equipment before and after CPFA, before and after hemoabsorption, and before hemofiltration. The plasma levels of TNF-α, IL-1β, IL-6, IL-10, interleukin-1 receptor antagonist (IL-1RA), soluble tumor necrosis factor receptor (sTNFR) I , and sTNFR-II from sites A, C, and E were determined with ELISA before CPFA was performed for the first time, and those from sites B and D were determined with ELISA after CPFA was performed for the first time. Plasma levels of the above-mentioned cytokines from sites A and B were determined with ELISA before CPFA and after CPFA was performed for the second time. The data of plasma levels of IL-1βP3, IL-1RA, sTNFR-I, sTNFR-II, and TNF-α before CPFA and after CPFA was performed for the second time were collected for calculation of the ratios of IL-1RA to IL-1β and sTNFR-I plus sTNFR-II to TNF-α. The expression rate of human leukocyte antigen DR (HLA-DR) on the CD14 positive monocytes, acute physiology and chronic health evaluation (APACHE) II score, body temperature, pulse, respiratory rate, and leukocyte count of patients were evaluated or recorded before CPFA and after CPFA was performed for the second time. Patients'condition was observed. Data were processed with paired t test.

RESULTSThe plasma levels of TNF-α, IL-1β, IL-6 and IL-10 from site B after CPFA was performed for the second time were significantly lower than those from site A before CPFA was performed for the first time (with t values respectively 7.05, 5.23, 4.73, 2.37, P values below 0.01). After CPFA was performed for the first time, the plasma levels of TNF-α, IL-1β, and IL-6 from site D were significantly lower than those from site C before CPFA was performed for the first time (with t values respectively 5.48, 2. 17, 1.78, P < 0.05 or P <0.01). The plasma levels of all cytokines were close between site B after CPFA was performed for the first time and site E before CPFA was performed for the first time (with t values from 0.04 to 1.05, P values above 0.05). The plasma levels of TNF-α, IL-1β, and IL-6 from site B after CPFA was performed for the second time were significantly lower than those from site A before CPFA was performed for the second time (with t values from 1.87 to 5.93, P <0.05 or P <0.01). The ratios of IL-1RA to IL-1β and sTNFR-I plus sTNFR-II to TNF-α, and expression rate of HLA-DR were increased significantly after CPFA was performed for the second time as compared with those before CPFA (with t values from 3.99 to 7. 80, P values below 0.01). APACHE II score after CPFA was performed for the second time was 11 ± 6, which was lower than that before CPFA (22 ± 7, t =4.63, P <0.01). After CPFA was performed for the second time, body temperature, pulse, and respiratory rate of patients were improved (with t values from 1.95 to 3.55, P values below 0.05) , and the leukocyte count was significantly decreased (t =4.36, P <0.01) as compared with those before CPFA. All patients survived and were discharged with length of stay of (27 ± 31) d, and no adverse effects occurred during CPFA treatment.

CONCLUSIONSCPFA, which combines hemoabsorption and hemofiltration, can facilitate the treatment of burn sepsis by decreasing the level of pro-inflammatory cytokines efficiently, alleviating systemic inflammatory response, and improving the immune status.

Adsorption ; Aged ; Biomarkers ; blood ; Burns ; blood ; complications ; immunology ; Cytokines ; blood ; Fluid Therapy ; Hemofiltration ; methods ; Hospitalization ; Humans ; Inflammation Mediators ; blood ; Interleukin 1 Receptor Antagonist Protein ; blood ; Interleukin-10 ; blood ; Interleukin-6 ; blood ; Sepsis ; blood ; immunology ; therapy ; Treatment Outcome ; Tumor Necrosis Factor-alpha

BACKGROUND: We intended to clarify the hypothesis that minimally invasive total hip arthroplasty (MI-THA) leads to less tissue damage and inflammatory response than does conventional total hip arthroplasty (C-THA). METHODS: We performed 30 cases of THA between September 2005 and May 2006 and evaluated these cases prospectively. We chose 15 MI-THA cases for the study group and another 15 C-THA cases for the control group. We checked skeletal muscle marker enzymes, such as serum creatinine kinase and aldolase, the pro-inflammatory cytokines, interleukin (IL)-6 and 8, and the anti-inflammatory cytokines, IL-10 and IL-1 receptor antagonist (ra) the day before surgery and at postoperative days 1, 7, and 14. RESULTS: On postoperative days 1 and 3, the study group showed significantly lower serum creatinine kinase, IL-6, IL-10, and IL-1ra values than those in the control group. Additionally, IL-8 was significantly lower on day 7 after surgery. CONCLUSIONS: These data show that MI-THA decreased the release of muscle marker enzymes due to tissue damage immediately after surgery and minimized the inflammatory response related to the surgery during the early postoperative period.
Adult ; Aged ; Aged, 80 and over ; Arthroplasty, Replacement, Hip/*adverse effects ; Biological Markers/blood ; Creatine Kinase/blood ; Female ; Fructose-Bisphosphate Aldolase/blood ; Humans ; Interleukin 1 Receptor Antagonist Protein/blood ; Interleukin-10/blood ; Interleukin-6/blood ; Interleukin-8/blood ; Male ; Middle Aged ; Minimally Invasive Surgical Procedures/adverse effects ; Soft Tissue Injuries/*blood/etiology

Interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor soluble receptors (sTNF-R) type I and II, and regulated upon activation, normal T-cell expressed and secreted (RANTES) play an important role in the modulation of primary glomerulonephritis (GN) course. The aim of the study was to assess whether pre-treatment measurements of IL-1ra, sTNF-R, and RANTES assessed conjointly may be useful as predicting factors in patients with GN. In 84 patients (45 males and 39 female) serum concentration (pg/mL) and urinary excretion (pg/mgCr) of cytokines were measured. After 12 months of therapy with steroids and cyclophosphamide the patients were divided into two subgroups: Responders (R) and Non-Responders (NR) according to the treatment results. The urinary IL-1ra, TNF-RI and RII were significantly higher in R than NR (1,732 vs 646 with P < 0.001, 13.1 vs 6.3 with P = 0.005, and 33.6 vs 14.4 with P = 0.012). The urinary RANTES excretion was increased in NR (79.6 vs 28.5; P < 0.001). The multivariable analysis showed that if conjointly assessed, only urinary IL-1ra, TNF-R I and R II, RANTES with 85% probability pointed the feature remission (R). In conclusion, the urinary excretion of IL-1ra, TNF-R I and R II, and RANTES examined conjointly are effective in predicting favorable response to immunosuppressive treatment in patients with GN.
Adult ; Cyclophosphamide/therapeutic use ; Female ; Glomerulonephritis/drug therapy/*metabolism/pathology ; Humans ; Immunosuppressive Agents/therapeutic use ; Interleukin 1 Receptor Antagonist Protein/*analysis/blood/urine ; Lymphocyte Activation ; Male ; Middle Aged ; Multivariate Analysis ; Predictive Value of Tests ; Receptors, Tumor Necrosis Factor, Type I/*analysis/blood/urine ; Receptors, Tumor Necrosis Factor, Type II/*analysis/blood/urine ; Steroids/therapeutic use ; T-Lymphocytes/immunology/metabolism

OBJECTIVE: To investigate the relationship between interleukin-1 (IL-1) system gene polymorphisms, and change in production of IL-1 by whole blood cells (WBCs), and bone mineral density (BMD) after hormone replacement therapy (HRT) in postmenopausal Korean women. METHODS: The IL-1alpha C(-889)T polymorphism, IL-1beta C(-511)T polymorphism and 86-base pair variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene was analyzed by restriction fragment length polymorphsim (REFLP), polymerase chain reaction-Genescan, and DNA sequencing in 206 postmenopausal Korean women receiving sequential HRT for 1 year. IL-1alpha, IL-1beta, and IL-1ra produced by WBCs cultured with lipopolysaccharide for 2 days, and serum CrossLaps (CTX), and osteocalcin were measured using enzyme-linked immunosorbent assay (ELISA) and immunoassay respectively. BMD at the lumbar spine and proximal femur was determined by dual energy X-ray absorptiometry. RESULTS: The IL-1 system genotypes were not distributed differently between HRT-responders and HRT-nonresponders (women who lose more than 3% of bone mass per year), and no differences in the annual percent change of BMD after HRT were noted among IL-1 system genotypes. After HRT, the production of IL-1alpha by WBCs decreased but no changes in the production of other components of IL-1 system were noted. There were no differences in the 6 month changes of bone turnover markers and the production of IL-1 system components by WBCs and IL-1beta/IL-1ra ratio after HRT across IL-1 system genotypes. Except a negative correlation between IL-1alpha with annual change of BMD at trochanter after HRT, the production of other components of IL-1 system by WBCs and their changes after HRT of 6 month did not correlated with annual change of BMD after HRT CONCLUSION: The IL-1 system gene polymorphisms do not affect change in BMD, and change in the production of ILs by WBCs after HRT in postmenopausal Korean women.
Absorptiometry, Photon ; Blood Cells ; Bone Density* ; Enzyme-Linked Immunosorbent Assay ; Female ; Femur ; Genotype ; Hormone Replacement Therapy* ; Humans ; Immunoassay ; Interleukin 1 Receptor Antagonist Protein ; Interleukin-1* ; Osteocalcin ; Sequence Analysis, DNA ; Spine ; Tandem Repeat Sequences

OBJECTIVETo study the distribution of variable numbers of tandem repeat (VNTR) polymorphism in the intron 2 and the single nucleotide polymorphism (SNP) at position +8006 in the exon 2 of IL-1RN in healthy Chinese Han Population of Wuhan province and to analyze their correlation with the serum lipoprotein level.

METHODSIL-1RN (VNTR) and IL-1RN (+8006) polymorphisms were detected by PCR and PCR-RFLP methods in 251 healthy Chinese Han Population of Wuhan, and the levels of serum lipoprotein, IL-1 and IL-1Ra were inspected simultaneously.

RESULTSIn IL-1RN (VNTR), allele I appeared most common, then allele II, and allele IV was rare. At the position of IL-1RN (+8006), allele T was most commonly seen followed by allele C. Allele II of IL-1RN (VNTR) always existed with allele C of IL-1RN (+8006). The levels of serum lipoprotein, IL-1 and IL-1Ra were not different among the different genotypes of the two polymorphisms.

CONCLUSIONThere were two gene polymorphisms in the intron 2 and exon 2 of IL-1RN, which were not correlated with the levels of serum lipoprotein, IL-1 and IL-1Ra. However, there seemed to be a linkage disequilibrium between IL-1RN (VNTR) and IL-1RN (+8006).

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Exons ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Hyperlipidemias ; blood ; genetics ; Interleukin 1 Receptor Antagonist Protein ; Introns ; genetics ; Lipoproteins ; blood ; Male ; Middle Aged ; Minisatellite Repeats ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Sialoglycoproteins ; genetics