Biological disease-modifying antirheumatic drugs in juvenile idiopathic arthritis of polyarticular course, enthesitis-related arthritis, and psoriatic arthritis: a consensus statement.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most common type of inflammatory arthritis in children. Treatment options have been expanded since the introduction of biologics, which are highly effective. The existing local JIA treatment guideline was published more than a decade ago, when use of biologics was not as common. In this article, we review the latest evidence on using biologics in three JIA subtypes: JIA of polyarticular course (pcJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). Based on the latest information, an update on eligibility, response assessment, termination, and safety information for using biologics in these patients was performed. CONSENSUS PROCESS: The JIA Work Group, which consisted of nine paediatricians experienced in managing JIA, was convened in 2016. Publications before July 2017 were screened. Eligible articles were clinical trials, extension studies, systemic reviews, and recommendations from international societies and regulatory agencies about the use of biologics in pcJIA, ERA, and PsA. Evidence extraction, appraisal, and drafting of propositions were performed by two reviewers. Extracted evidence and drafted propositions were presented and discussed at the first two meetings. Overwhelming consensus was obtained at the final meeting in May 2018. Seven practice consensus statements were formulated. Regular review should be performed to keep the practice evidence-based and up-to-date.

Detection methods of Cyprinid herpesvirus 2 infection in silver crucian carp (Carassius auratus gibelio) via a pORF72 monoclonal antibody.

Cyprinid herpesvirus 2 (CyHV-2) is the main pathogen responsible for causing haematopoietic necrosis disease in Carassius auratus gibelio. Although many nucleic acid-based diagnostic methods have been applied, no stable and sensitive immunological diagnostic approaches have been reported. In this study, to detect CyHV-2 in clinical samples using immunological methods, recombinant ORF72 protein (pORF72), encoded by the CyHV-2 ORF72 gene, was used as a capture antigen to identify blood and tissues infected with CyHV-2. First, ORF72 gene was amplified from the CyHV-2 genome and cloned into a PGEX-4t-3 expression vector to produce pORF72 in Escherichia coli. The purified pORF72 was used as an immunogen to prepare monoclonal antibodies. The Western blotting assays revealed that the monoclonal antibody could specifically identify the pORF72. Furthermore, an immunohistochemical protocol and a blood smear method were established to detect CyHV-2 in carps. The results indicate that the monoclonal antibody against pORF72 could be utilized as an effective detection tool for haematopoietic necrosis disease in Carassius auratus gibelio.

S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis.

BACKGROUND: S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin. METHODS: Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m(-2) followed by oxaliplatin 85 mg m(-2) on day 1 and S-1 80 mg m(-2) per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed. RESULTS: Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4-81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60. CONCLUSION: The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.

Reduced antibody formation after influenza vaccination in patients with neuromyelitis optica spectrum disorder treated with rituximab.

BACKGROUND AND PURPOSE: Vaccination against infection becomes important in patients with neuromyelitis optica spectrum disorder (NMOSD) because they are at an increased risk of infection due to long-term immunosuppressive therapy. However, it is unclear whether NMOSD patients under immunosuppression therapy show proper antibody formation after vaccination. Thus the antibody formation after influenza A (H1N1) vaccination in patients with NMOSD receiving rituximab was evaluated. METHODS: The study enrolled 26 patients with NMOSD, nine with multiple sclerosis and eight healthy controls. The enrolled patients had been treated with rituximab (n = 16), mycophenolate mofetil (n = 5), azathioprine (n = 6) and interferon-ß (IFN-ß) (n = 8). Antibodies against the H1N1 influenza virus were measured in the serum drawn just before (T0) and between 3 and 5 weeks after (T1) vaccination. The immunization states for hepatitis B virus surface antigen, measles and tetanus during the treatment period were also tested. RESULTS: The rituximab group showed significantly lower geometric mean titer, seroprotection rate and mean fold increase than the azathioprine group, IFN-ß group and healthy controls, and a lower seroconversion rate than the IFN-ß group. This decrease in vaccination efficacy was also shown in patients receiving mycophenolate mofetil. The immunization state for hepatitis B virus surface antigen, measles and tetanus remained the same during the treatment period with each drug, suggesting that these treatments do not affect previously formed immunity. CONCLUSION: This study shows a severely hampered humoral immune response to H1N1 influenza vaccine in patients with NMOSD treated with rituximab, although the vaccination itself is safe in these patients.

CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients.

BACKGROUND: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. METHODS: Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). RESULTS: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. CONCLUSION: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Phase II study of a triplet regimen of S-1 combined with irinotecan and oxaliplatin in patients with metastatic gastric cancer: clinical and pharmacogenetic results.

BACKGROUND: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. PATIENTS AND METHODS: Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. RESULTS: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). CONCLUSIONS: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

Acupuncture for Bell's palsy.

BACKGROUND: Bell's palsy or idiopathic facial palsy is an acute facial paralysis due to inflammation of the facial nerve. A number of studies published in China have suggested acupuncture is beneficial for facial palsy. OBJECTIVES: The objective of this review was to examine the efficacy of acupuncture in hastening recovery and reducing long-term morbidity from Bell's palsy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to April 2006), EMBASE (January 1980 to April 2006), LILACS (from January 1982 to April 2006) and the Chinese Biomedical Retrieval System (January 1978 to April 2006) for randomised controlled trials using 'Bell's palsy' and its synonyms, 'idiopathic facial paralysis' or 'facial palsy' as well as search terms including 'acupuncture'. Chinese journals in which we thought we might find randomised controlled trials or controlled clinical trials relevant to our study were handsearched. We reviewed the bibliographies of the randomised trials and contacted the authors and known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: We included all randomised or quasi-randomised controlled trials involving acupuncture in the treatment of Bell's palsy irrespective of any language restrictions. DATA COLLECTION AND ANALYSIS: Two review authors identified potential articles from the literature search and extracted data independently using a data extraction form. The assessment of methodological quality included allocation concealment, patient blinding, differences at baseline of the experimental groups and completeness of follow-up. Two review authors assessed quality independently. All disagreements were resolved by discussion between the review authors. MAIN RESULTS: Six studies including a total of 537 participants met the inclusion criteria. Five of them used acupuncture while another one used acupuncture combined with drugs. No trials reported on the outcomes specified for this review. Harmful side effects were not reported in any of the trials. Flaws in study design or reporting (particularly uncertain allocation concealment and substantial loss to follow-up) and clinical differences between trials prevented conclusions about the efficacy of acupuncture. AUTHORS' CONCLUSIONS: The quality of the included trials was inadequate to allow any conclusion about the efficacy of acupuncture. More research with high quality trials is needed.

Measurement of synovial fluid volume using urea.

OBJECTIVE: To examine the utility of using urea concentrations for determining Synovial Fluid (SF) joint volume in effused and non-effused joints. METHODS: Knee joint SF was aspirated from 159 human study participants with symptomatic osteoarthritis of at least one knee either directly (165 knees) or by lavage (110 knees). Serum was obtained immediately prior to SF aspiration. Participants were asked to rate individual knee pain, aching or stiffness. SF and serum urea levels were determined using a specific enzymatic method run on an automated CMA600 analyzer. Cell counts were performed on direct SF aspirates when volume permitted. The formula for calculating SF joint volume was as follows: V(j)=C(D)(V(I))/(C-C(D)) with V(j)=volume of SF in entire joint, C(D)=concentration of urea in diluted (lavage) SF, V(I)=volume of saline injected into joint, and C=concentration of urea in undiluted (neat) SF derived below where C=0.897(C(S)) and C(s)=concentration of urea in serum. RESULTS: There was an excellent correlation (r(2)=0.8588) between SF and serum urea in the direct aspirates with a ratio of 0.897 (SF/serum). Neither urea levels nor the SF/serum ratio showed any correlation with Kellgren Lawrence (KL) grade, or cell count. While urea levels increased with age there was no change in the ratio. Intraarticular SF volumes calculated for the lavaged knees ranged from 0.555 to 71.71ml with a median volume of 3.048ml. There was no correlation of SF volume to KL grade but there was a positive correlation (P=0.001) between SF volume and self-reported individual knee pain. CONCLUSION: Our urea results for direct aspirates indicate an equilibrium state between serum and SF with regard to the water fraction. This equilibrium exists regardless of disease status (KL grade), inflammation (cell count), or age, making it possible to calculate intraarticular volume of lavaged joints based upon this urea method. Most of the joint volumes we calculated fell within the previously reported range for normal knees of 0.5-4.0ml. The positive correlation between SF volume and knee symptoms reinforces the clinical utility of this method for quantifying SF volume.

Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis.

OBJECTIVE: To evaluate diurnal variation of biomarkers in subjects with osteoarthritis (OA) of the knee. METHODS: Twenty subjects with radiographic knee OA were admitted to the General Clinical Research Center of Duke University for an overnight stay to undergo serial blood and urine sampling. Biomarkers measured included serum hyaluronan (HA), cartilage oligomeric matrix protein (COMP), keratan sulfate (KS-5D4), aggrecan neoepitope (CS846), high-sensitivity C-reactive protein (hsCRP), osteocalcin, transforming growth factor beta1 (TGFbeta1), and type II collagen (CII)-related epitopes (neoepitope from cleavage of CII [C2C], carboxy-terminus of three-quarter peptide from cleavage of CI and CII [C1,2C], and type II procollagen carboxy-propeptide [CPII] in serum, and C-terminal telopeptides of CII [CTX-II] and C2C in urine). RESULTS: Levels of serum HA, COMP, KS-5D4, and TGFbeta1 increased significantly from T0 (before arising from bed) to T1 (1 hour after arising). More diurnal variation in HA was observed in patients with higher daily mean HA concentrations. CPII increased significantly from T0 to T2 (4 hours after arising). Urinary concentrations of CTX-II were also found to vary with morning activity, decreasing significantly from T0 to T2. Urinary C2C concentrations increased significantly from T0 until T3 (early evening). No diurnal variations in CS846, hsCRP, osteocalcin, serum C2C, or C1,2C were observed. Six biomarkers (serum C2C, C1,2C, COMP, KS-5D4, TGFbeta1, and urinary CTX-II) were associated with radiographic knee OA (expressed as the sum of Kellgren/Lawrence radiographic severity grades), with the strongest correlations observed with measurements obtained at later time points (either T2 or T3). CONCLUSION: Our study results suggest that serum and urine sampling for HA, COMP, KS-5D4, TGFbeta1, CPII, urinary CTX-II, and urinary C2C should be standardized in future OA clinical trials. Serum and urine sampling at late midday time points may be the optimal approach for OA studies, although this result should be validated in a larger cohort.

Serum HER-2 concentration in patients with primary breast cancer.

OBJECTIVE: To evaluate whether serum HER-2/neu (HER-2) concentration is a valid index of HER-2 status in women with primary breast cancer, and to establish a normal reference range for serum HER-2 concentration in Korean women. METHODS: Serum HER-2 concentration was measured and immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) carried out on tissue samples from 86 consecutive female patients. The results of the three datasets were compared. The cut off value of HER-2 concentration was determined from the mean +2SD values derived from the serum of 93 healthy volunteers. RESULTS: The IHC and FISH data were significantly correlated (p<0.01), but neither showed significant correlation with the serum HER-2 data. The cut off value of serum HER-2 was 10.2 microg/l, and the serum HER-2 concentration of patients with primary breast cancer ranged from 5.0 to 17.5 microg/l. Only five patients had a serum HER-2 value above the cut off value. CONCLUSIONS: Serum HER-2 concentration cannot be substituted for IHC or FISH to evaluate HER-2 status, nor can it be used as a diagnostic tumour marker in primary breast cancer, considering the low prevalence of serum HER-2 elevation.