Characteristic alterations of gut microbiota in uncontrolled gout.

Microbiome research has been on the rise recently for a more in-depth understanding of gout. Meanwhile, there is a need to understand the gut microbiome related to uric acid-lowering drug resistance. In this study, 16S rRNA gene-based microbiota analysis was performed for a total of 65 stool samples from 17 healthy controls and 48 febuxostat-treated gout patients (including 28 controlled subjects with decreased uric acid levels and 20 uncontrolled subjects with non-reduced uric acid levels). Alpha diversity of bacterial community decreased in the healthy control, controlled, and uncontrolled groups. In the case of beta diversity, the bacterial community was significantly different among groups (healthy control, controlled, and uncontrolled groups). Taxonomic biomarker analysis revealed the increased population of g-Bifidobacterium in healthy controls and g-Prevotella in uncontrolled patients. PCR further confirmed this result at the species level. Additionally, functional metagenomics predictions led to the exploration of various functional biomarkers, including purine metabolism. The results of this study can serve as a basis for developing potential new strategies for diagnosing and treating gout from microbiome prospects.

Pulmonary amyloidosis and multiple myeloma mimicking lymphoma in a patient with Sjogren's syndrome: A case report.

BACKGROUND: Sjogren's syndrome (SS), which affect salivary gland function, is an autoimmune disease. SS may involve extraglandular organs. Approximately 10 to 20 percent of SS patients have clinically significant lung disease, but presentation of pulmonary amylodosis is extremly rare. The incidence of benign monoclonal gammopathy in SS patients is high, but multiple myeloma is rare. No case involving the simultaneous occurrence of two rare diseases, pulmonary amyloidosis and multiple myeloma, in the same patient with SS has been reported so far. CASE SUMMARY: A 41-year-old male patient was referred to our hematology department due to incidentally detected gastric plasmacytoma. He had been diagnosed with SS four years earlier. Multiple miliary nodules, ground glass opacity in both lung fields, and enlargement of both inguinal lymph nodes was observed on chest and abdomen computer tomography. Based on the pathological findings of lung and lymph node biopsied specimens, the patient was diagnosed with pulmonary amyloidosis and multiple myeloma. Pulmonary amyloidosis and multiple myeloma associated with SS has rarely been reported. CONCLUSION: This is an extremely rare case of simultaneous pulmonary amyloidosis and multiple myeloma in the same patient with SS.

Metformin as a Treatment Strategy for Sjögren's Syndrome.

Sjögren's syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.

Comparison of the efficacy and safety of CELBESTA® versus CELEBREX® in patients with rheumatoid arthritis: a 6-week, multicenter, double-blind, double-dummy, active-controlled, randomized, parallel-group, non-inferiority phase 4 clinical trial.

OBJECTIVES: Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor that is commonly used to reduce the incidence of gastrointestinal (GI) complications in patients with rheumatoid arthritis (RA). CELBESTA® is a generic equivalent to CELEBREX®, a celecoxib preparation. This study compared the efficacy and safety of CELBESTA® and CELEBREX® in patients with RA. METHODS: This was a multicenter, double-blind, double-dummy, active-controlled, randomized, parallel-group, non-inferiority clinical trial. The primary endpoint was a change from baseline in self-assessed pain intensity determined using a 100-mm visual analog scale after 6 weeks of treatment. RESULTS: After a washout period, 119 eligible subjects were randomized to one of two groups (CELBESTA® group, n = 61; CELEBREX® group, n = 58). CELBESTA® was not inferior to CELEBREX® because the upper limit of two-sided 95% confidence interval (CI) for the difference between the two groups (difference in the least square [LS] mean, -8.68 mm; two-sided 95% CI -16.59 mm to -0.77 mm) was less than the non-inferiority margin (10 mm). There were no significant differences in GI complications and renal toxicity. CONCLUSIONS: CELBESTA® was not inferior to CELEBREX® with regard to the pain relief efficacy in RA patients, and the tolerability and safety profiles were excellent and at similar levels for both preparations.

[Musculoskeletal Manifestation in Inflammatory Bowel Disease].

Almost 50% of patients with inflammatory bowel disease (IBD) exhibit at least one extra-intestinal manifestation in their lifetime. Extra-intestinal manifestations of IBD are often associated with the intestinal disease activity, reducing the quality of life of the patient but rarely leading to fatal complications. Musculoskeletal involvement is the most frequent extra-intestinal manifestation of patients with IBD but this rarely occurs before IBD is diagnosed. They are manifested in various forms, such as arthropathy, fibromyalgia, and osteoporosis. Therefore, a multidisciplinary team approach including gastroenterologists and rheumatologists are necessary for optimal treatment. This review focuses on the diagnosis and treatment of musculoskeletal manifestations of IBD from the perspectives of rheumatologists who can assist gastroenterologists.

Standardized, musculoskeletal ultrasonographic reference values for healthy Korean adults.

BACKGROUND/AIMS: To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. METHODS: A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. RESULTS: The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. CONCLUSION: We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Efficacy and safety of mycophenolate mofetil and tacrolimus combination therapy in patients with lupus nephritis: a nationwide multicentre study.

OBJECTIVES: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (TAC) may be an option for lupus nephritis (LN) patients that do not adequately respond to initial treatment. We evaluated the efficacy and safety of the combination treatment of MMF and TAC in LN patients with suboptimal response to prior MMF or TAC treatments. METHODS: In this multicentre study, we retrospectively enrolled 62 patients with class III, IV, or V LN who inadequately responded to MMF or TAC treatment. Those patients were then treated with a combination of MMF and TAC for 6 months. The primary outcome was complete remission (CR) at 6 months, and secondary outcomes included overall response and adverse events. RESULTS: After 6 months of treatment with the drug combination, CR was achieved in 14 of 62 patients (22.6%), and 35 (56.5%) patients responded. A significant reduction in proteinuria and lupus disease activity score was observable after 3 months. After 1 year, the CR rate increased to 36.4% (20 of 55 patients), and the overall response rate (n=38, 69.1%) also increased from 6 months. Twenty-one patients reported 29 adverse events, including severe infection requiring hospitalisation (n=3, 10.3%), infection not requiring hospitalisation (n=2, 6.9%), and herpes zoster (n=4, 13.8%). CONCLUSIONS: Our findings suggest that a combined MMF and TAC treatment, with a favourable adverse-event profile, may be a beneficial option for LN patients with inadequate response to either MMF or TAC treatments.

Effects of Rifampin and Doxycycline Treatments in Patients With Uncomplicated Scrub Typhus: An Open-Label, Randomized, Controlled Trial.

Background: Doxycycline is currently the most frequently used treatment in patients with scrub typhus. However, doxycycline-resistant strains have been found, necessitating the development of a new treatment. Rifampin is known to be effective even for such strains. Our aim in this study was to compare the effects of rifampin and doxycycline treatment in patients with scrub typhus in areas in which resistance to doxycycline has not been reported. Methods: Patients admitted to Chosun University Hospital and regional network hospitals between 2007 and 2009 with a body temperature ≥37.5°C and suspected to have scrub typhus were randomly assigned to 1 of 2 treatment groups: a group administered doxycycline 100 mg twice daily for 5 days and a group administered rifampin 600 mg once daily for 5 days. For treatment outcomes, fever, headache, muscle ache, and rash clearance times were compared between the groups. Results: The rifampin and doxycycline groups showed equivalence in all treatment outcomes evaluated. The proportions of patients with fever clearance within 48 hours were similar between groups. Furthermore, there was no significant difference in the occurrence of side effects following drug administration between groups. Conclusions: On the basis of the finding that equivalent treatment effects and safety were found in patient groups that received 600 mg of rifampin and 200 mg of doxycycline, respectively, for 5 days to treat scrub typhus, rifampin may be considered an alternative treatment to doxycycline. Clinical Trials Registration: NCT00568711.

Systemic sclerosis due to crystalline silica exposure among jewelry workers in Korea: two case reports.

BACKGROUND: Occupational exposure to crystalline silica is a potential risk factor for various systemic autoimmune diseases including systemic sclerosis. The etiology of systemic sclerosis is not conclusively known, but there are epidemiological studies that show the relationship between exposure to crystalline silica and risk of systemic sclerosis. Here we report, for the first time, two cases of crystalline silica-related systemic sclerosis in patients who worked in crystal processing in the jewelry-manufacturing field. CASE PRESENTATION: Case 1 is a 57-year-old man who had worked mainly in crystal processing for multiple jewelry-processing companies for 17 years, since the age of 15 years. He contracted tuberculosis at the age of 25 years and showed Raynaud's phenomenon of both the hands and feet at age 32 years. Digital cyanosis and sclerosis developed at approximately age 41 years. The patient was diagnosed with systemic sclerosis at age 48 years. Case 2 is a 52-year-old man who worked in crystal processing for various jewelry-processing companies for 7 years, since the age of 23 years. He first showed signs of cyanosis in the third and fourth digits of both hands at age 32 years, was diagnosed with Raynaud's syndrome at age 37 years, and was diagnosed with systemic sclerosis at age 38 years. Crystal processing is a detailed process that involves slabbing and trimming the selected amethyst and quartz crystals, which requires close proximity of the worker's face with the target area. In the 1980s and 1990s, the working hours were 12 h per day, and the working environment involved 15 workers crowded into a small, 70-m2 space with poor ventilation. CONCLUSION: Two workers who processed crystals with a maximum crystalline silica content of 56.66% developed systemic sclerosis. Considering the epidemiological and experimental evidence, exposure to crystalline silica dust was an important risk factor for systemic sclerosis. An active intervention is necessary to reduce exposure in similar exposure groups in the field of jewelry processing.

Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.

BACKGROUND/AIMS: Gout is a common inf lammatory arthritis triggered by the crystallization of uric acid in the joints. Serum uric acid levels are highly heritable, suggesting a strong genetic component. Independent studies to confirm the genetic associations with gout in various ethnic populations are warranted. We investigated the association of polymorphisms in the ABCG2 and SLC2A9 genes with gout in Korean patients and healthy individuals. METHODS: We consecutively enrolled 109 patients with gout and 102 healthy controls. The diagnosis of gout was based on the preliminary criteria of the America College of Rheumatology. Genomic DNA was extracted from whole blood samples. We identified single nucleotide polymorphism (SNP) changes in the ABCG2 and SLC2A9 genes using a direct sequencing technique. rs2231142 in ABCG2 and rs6449213 and rs16890979 in SLC2A9 and nearby regions were amplified by polymerase chain reaction. RESULTS: Patients with gout had significantly higher A/A genotype (29.3% vs. 4.9%, respectively) and A allele (52.8% vs. 26.5%, respectively) frequencies of rs2231142 in ABCG2 than did controls (χ(2) = 29.42, p < 0.001; odds ratio, 3.32; 95% confidence interval, 2.11 to 5.20). We found novel polymorphisms (c.881A>G and c.1002+78G>A) in the SLC2A9 gene. The univariate logistic regression analysis revealed that the c.881A>G and c.1002+78G>A SNPs were significantly higher in patients than in controls. CONCLUSIONS: We demonstrated a significant association between rs2231142 in the ABCG2 gene and gout and identified novel SNPs, c.881A>G and c.1002+78G>A, in the SLC2A9 gene that may be associated with gout in a Korean population.

Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines.

The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.

Unilateral Pedicle Fracture Accompanying Spondylolytic Spondylolisthesis.

Unilateral pedicle stress fracture accompanying spondylolytic spondylolisthesis is rare even in the elderly. Most are associated with major trauma, previous spine surgery, or stress-related activity. Here, the authors describe an unique case of unilateral pedicle fracture associated with spondylolytic spondylolisthesis at the L5 level, which was successfully treated by posterior lumbar interbody fusion with screw fixation at the L5-S1 level. As far as the authors' knowledge, no such case has been previously reported in the literature. The pathophysiological mechanism of this uncommon entity is discussed and a review of relevant literature is included.

Brown-séquard syndrome caused by a cervical synovial cyst.

Synovial cysts are recognized as an uncommon cause of radicular and myelopathic symptoms. They are most frequently found in the lumbar region. The cervical spine or cervicothoracic junction is a rare location for a degenerative intraspinal synovial cyst as compared with the lumbar spine. At given cervical spinal levels, synovial cysts probably share clinical features with disc herniation and stenosis. However, the pathogenesis of synovial cysts remains still controversial. Here, we report a rare case of a synovial cyst in the lower cervical spine presented as Brown-Séquard syndrome and include a brief review of the literature. To the best of our knowledge, no previous report has been issued in the English literature on a synovial cyst presenting with Brown-Séquard syndrome. Neurologic function recovered completely after complete removal of the cyst and expansive laminoplasty.

Clinical characteristics and prognostic factors for relapse in patients with polymyalgia rheumatica (PMR).

Polymyalgia rheumatica (PMR) is a common inflammatory disease of the elderly in western countries, but the prevalence is apparently different between races and countries. Until now, an epidemiologic study of PMR is limited in Korea. We retrospectively evaluated the clinical data of 78 patients with PMR who were treated in 5 tertiary hospitals, and analyzed initial laboratory data, symptoms, therapeutic responses, and prognostic factors for relapse 1 year after treatments. Sixty percent of patients had pain in both shoulder and hip girdles with 10.6 weeks of duration, 75.9 ± 32.7 mm/h of erythrocyte sedimentation rate (ESR), and 6.2 ± 6.4 mg/dl of C-reactive protein. The rate of relapse and remission at 1 year was 38.4 and 2.5 %, respectively. The rate of overall relapse was 46.1 %, and the relapse occurred mostly in a year, especially between 6 and 12 months after diagnosis. There were more female in relapse group (88.9 %, p = 0.037), and cumulative steroid dose of 1 year was significantly higher in relapse group (5.5 ± 2.7 vs. 4.4 ± 2.5 g, p = 0.018). Independent risk factors for relapse were initial CRP ≥ 2.5 mg/dl (OR 6.296, p = 0.047) and the use of hydroxychloroquine (OR 6.798, p = 0.035). Initial dosage or tapering speed of steroid did not influence on prognosis. In Korean patients with PMR, baseline clinical characteristics and relapse rate were similar to previous studies, but our patients accompanied no giant cell arteritis and showed lower remission rate as well as delayed therapeutic response and later occurrence of relapse. More aggressive management would be needed according to the clinical status of patients.

Sternocostal involvement in chronic recurrent multifocal osteomyelitis associated with ulcerative colitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is a chronic, relapsing, inflammatory, non-infectious disorder of the skeletal system and is of unknown origin. Early diagnosis of the disease is essential to exact treatment. The relationship between inflammatory bowel disease and CRMO is understood as extraintestinal rheumatic manifestations. CRMO associated with ulcerative colitis (UC) is very rarely reported. This case is first report of sternocostal involvement in CRMO associated with UC.

Clinical analysis of microscopic removal of discal cyst.

OBJECTIVE: The purpose of this study was to evaluate the clinical presentation and surgical outcome in patients with symptomatic discal cyst. METHODS: The authors reviewed consequent 9 patients in whom microscopic excision of the discal cyst with or without additional discectomy for discal cyst from 2005 to 2012. Diagnostic imagings including simple radiographs, computed tomography with discogram and magnetic resonance images were performed in each case. The patients were reviewed to evaluate the clinical presentation, surgical outcome and related complications. RESULTS: In all patients, discal cyst was located in the lumbar region and they presented with back pain and unilateral radiating pain. The preoperative magnetic resonance images (MRI) and computed tomography (CT) scan with discogram showed a connection between the cyst and the involved intervertebral disc. All patients obtained immediate relief of symptoms after microscopic excision of discal cyst. There were no recurrent lesions during follow-up period. The mean preoperative visual analogue scale (VAS) was 7.8 when compared with 2.6 in preoperative assessment. All patients obtained excellent or good outcome according to modified MacNab's criteria. CONCLUSION: Discal cysts are rare lesions that can lead to back pain and refractory sciatica. Microscopic excision of the cyst can achieve remarkable improvement of symptoms.

Site-directed modification of the adenylation domain of the fusaricidin nonribosomal peptide synthetase for enhanced production of fusaricidin analogs.

Fusaricidins produced by Paenibacillus polymyxa DBB1709 are lipopeptide antibiotics active against fungi and Gram-positive bacteria. The cyclic hexapeptide structures of fusaricidins are synthesized by fusaricidin synthetase, a non-ribosomal peptide synthetase. The adenylation domain of the third module (FusA-A3) can recruit L: -Tyr, L: -Val, L: -Ile, L: -allo-Ile, or L: -Phe, which diversifies the fusaricidin structures. Since the L: -Phe-incorporated fusaricidin analog (LI-F07) exhibits more potent antimicrobial activity than other analogs, we modified a specificity-conferring sequence in the substrate binding pocket of FusA-A3 to direct the enhanced production of LI-F07. Base on comparison to the adenylation domain of gramicidin S synthetase 1 and tyrocidine synthetase 1, both of which mainly activate L: -Phe, six mutant strains with altered FusA-A3 were generated using site-directed mutagenesis. M3 (I239W, I299V), M5 (I299V, G322A, V330I), and M6 (S239W, I299V, G322A, V330I) mutants produced significantly more LI-F07 than the wild-type strain.