Abstract Background Increasing evidence demonstrated that inflammatory bowel disease (IBD) has a shared genetic background with autoimmune rheumatic diseases (ARDs). However, the association between these two disease entities is not vigorously elucidated. The aim of this study is to investigate the prevalence and association between IBD and ARDs. Methods A nationwide population-based cross-sectional study was performed using the Korean National Health Insurance Claims database according to ICD-10 codes (Table 1). The prevalence of ARDs, including systemic lupus erythematosus (SLE), inflammatory myositis (polymyositis (PM) and dermatomyositis (DM)), systemic sclerosis (SSc), Sjogren’s syndrome (SjS), ankylosing spondylitis (AS), and rheumatoid arthritis (RA), was determined in patients with inflammatory bowel disease, compared with general populations. Results A total of 82,480 IBD patients (57,382 patients with ulcerative colitis and 25,098 with Crohn’s disease) were enrolled. The analysis revealed that patient with IBD had higher risk of being concomitantly affected by AS and RA (Table 2). Other ARDs, such as SLE, inflammatory myositis, SSc, and SjS were not associated with IBD. Conclusion This nationwide population-based study demonstrated that RA and AS showed higher incidence in IBD patients. This result suggests that etiopathogenesis of IBD might be shared with RA and AS.

Early colorectal cancer is defined as a carcinoma confined to the submucosa, regardless of lymph node (LN) status. The risk of LN metastasis in early colon cancer is ranging from 6.3% to 17%, and submucosal invasion more than 1000um, lymphovascular invasion (LVI), poor differentiation and tumor budding are well-known risk factor. We aimed to clarify the risk factors for LN metastasisin early colorectal cancer.

We report the first known ethnic Malay patient with laminin alpha-2 (merosin) deficiency (MDC1A), a subtype of congenital muscular dystrophy (CMD) as a result of novel LAMA2 gene mutations. The 21-month-old female presented with hypotonia at birth and gross motor delay of her distal lower limbs. Physical examination showed generalised hypotonia, hyporeflexia and myopathic facies but good cognitive functions. Serum creatine kinase was elevated and white matter changes were detected in the brain MRI. Muscle biopsy showed dystrophic changes with complete laminin alpha 2 deficiency by immunohistochemistry. Mutation analysis of LAMA2 showed compound heterozygote at exon 21, c. 2888delG(p. Gly963Alafs*111) and exon 34, c. 4886dupC(p. Pro1629Profs*40) leading to premature stop codon for each of the frameshift mutations. Patient review at seven years of age showed satisfactory cognitive functions despite having contractures and weakness. Genetic testing of LAMA2 related muscular dystrophy facilitated the earlier diagnosis of MDC1A and genetic counselling for this family.

Background Several pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 and IL-15 are known to be critical in synovial inflammatory process in RA and successful results have been obtained in RA treatment with targeting pro-inflammatory cytokines including TNF-α, IL-1 and IL-6. Objectives This study sought to investigate the role of IL-33 and IL-6 in RA patients receiving IL-6 receptor inhibition therapy. Methods We analyzed the association of the IL-33 and IL-6 level with disease activity and serologic features in 83 patients with RA. We also measured the serum level of IL-33 and IL-6 before and after the administration of tocilizumab for 24 weeks in 40 patients. Results Serum IL-33 level showed significant correlation with RF (rho =0.660, p<0.001) but did not correlate with DAS28, ESR, hsCRP or RA duration. IL-6 level was significantly correlated with hsCRP (rho =0.482, p<0.001) but not correlate with DAS28, ESR, RF or RA duration. There was no correlation between serum IL-6 and IL-33 levels. Serum IL-33 level significantly decreased after 24 weeks of IL-6 receptor inhibition in patients with RA (p<0.001). When comparing subgroups according to ACR20 response, serum IL-33 levels were significantly decreased after 24 weeks of IL-6 receptor inhibition therapy in ACR20 responders (p<0.001) but not in the non-responders (p=0.084). Baseline IL-33 levels were not significantly different between the two subgroups (p=0.765). Serum IL-6 levels were not significantly changed after 24 weeks of IL-6 receptor inhibition therapy (median 7.1 to 8.9 pg/mL, p=0.503). Changes of IL-6 levels were insignificant both in ACR20 responders and non-responders after 24 weeks of IL-6 receptor inhibition therapy. Baseline IL-6 levels were not different between ACR20 responders and non-responders. Conclusions The use of IL-6 receptor inhibitor decreased the serum level of IL-33 and this effect seems to be led by the responder group. IL-33 could be a useful indicator to monitor the response in IL-6 receptor inhibition therapy. Disclosure of Interest None declared

Background: Congenital myopathies (CMPs) are a group of rare inherited myopathies caused by heterogenous genetic etiologies. Objective: In this study, we aimed to identify subtypes and genotypes of CMPs from our muscle biopsy depository. Patients and Methods: We have reviewed our muscle biopsy record and selected cases of CMPs based on clinical and pathological findings. For the selected cases, either targeted sequencing or whole exome sequencing (WES) was performed in order to identify the genetic cause. This study was approved by institutional review board of PNUYH. Results: From 1999 to 2015, 33 cases of CMPs were diagnosed among 773 muscle biopsies (∼4%). The subtypes and numbers of each type of CMPs are as follows; nemaline myopathy (15), central core disease (5), centronuclear myopathy (5), core-rod myopathy (3), congenital fiber type disproportion syndrome (2), myotubular myopathy (1), cap myopathy (1), and rigid spine syndrome (1). Among them, causative mutations were identified in 17 cases. Conclusion: Our study suggests current technological limitation of WES in the genetic diagnosis of individual patient with CMP, especially when the causative gene is still illusive, extremely large, or has long repetitive sequences. For example, we were only able to identify NEB mutations in both allele of six patients among 13 patients with autosomal recessive nemaline myopathies. In other five, only single NEB mutation was identified, and no mutation was identified in the other two. Our study shows careful sequencing strategy combining Sanger sequencing and WES is still essential in genetic diagnosis of CMPs.

Background Tocilizumab (TCZ) has been developed and investigated in several clinical trials for efficacy and adverse events in RA patients. But it remains to be investigated which biomarkers have early predictive values. Objectives To investigate predictive cytokines of TCZ therapy in rheumatoid arthritis (RA) patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). Methods We collected sera as part of CWP-TCZ301, a 24-week, randomized, double–blinded trial of TCZ in RA patients with an inadequate response to DMARDs. Serum levels of cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-17A, IL-21 and IL-23 were determined by luminex multiplex analysis at baseline and after treatment (4, 12 and 24 weeks). IL-6 and soluble IL-6 receptor (sIL-6R) were measured by ELISA. Therapeutic response was evaluated by American College of Rheumatology 20% improvement (ACR20) in the TCZ group (n=47) and placebo group (n=48) after 24 weeks. Results Early withdrawal patients from the study were excluded in the evaluation. In TCZ group (n=40), 29 patients were ACR20 responders and 11 patients were non-responders after 24 weeks of treatment. Baseline serum levels of IL-17A were significantly lower in responders than in non-responders (p <0.05). However IL-17A level did not significantly change during TCZ treatment irrespective of ACR20 response. Levels of IL-21 and IL-23 were not significantly different at baseline in responders and non-responders. However, they were significantly decreased at 12 and 24 weeks in responders (all p <0.005), but not in the non-responders. In the placebo group (n=43), 8 patients were ACR20 responders and 35 patients were non-responders after 24 weeks of treatment. Baseline serum levels of IL-17A and IL-21 in ACR20 responders were significantly lower than in non-responders (p<0.001 and p=0.001, respectively). But they did not significantly change during DMARDs treatment, irrespective of ACR20 response. Multivariable logistic regression analysis showed that lower baseline IL-17A patients had increased the odds ratio of being a responder after TCZ (OR 7.364) as well as placebo (OR 9.333) treatment. Conclusions Baseline serum level of IL-17A could be used to predict response of TCZ and DMARDs therapy in RA patients. References Zhou L, Ivanov, II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8(9):967-74. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5095

Nemaline myopathy (NM) is a clinically heterogeneous congenital myopathy characterized by the presence of nemaline rods in the skeletal muscle fibers. We investigated the clinical variation and pathological features in Korean patients with NM. Thirteen patients were diagnosed through muscle biopsy. Six patients had the typical congenital type, which showed the motor development delay and hypotonia at birth. Six patients showed the mild childhood type with the gait disturbance. One patient had the intermediate congenital type, who needed mechanical ventilation. Regarding the distribution of weakness, five patients presented distal dominant weakness across the clinical type. High arched palates and feet deformity were observed. Equino varus deformity was identified in two patients. But, we could not find the cardiac muscle involvement. Typical nemaline rods were recognized on light microscopy with muscle biopsy from 11 patients. However, we could identify the nemaline filamentous aggregation in electro microscope (EM) from 2 patients. One of them showed a mitochondrial abnormality in EM. Type 1 fiber predominance was in all patients. The causative mutation form 8 patients was investigated, we found a missense heterozygous mutation in exon 1 of TPM3 gene (c.32T>A, p.Met11Lys). Seven patients showed negative results in ACTA1 gene. The thirteen patients in this study did not share much common feature except the dysmorphic appearance. The clinical diversity was prominent with the distribution of muscle weakness and the severity of respiratory dysfunction. This study showed the phenotypic heterogeneity of NM is not only with clinical features but also with pathological findings in our patient pool. Wider application of whole exome sequencing may help overcome the phenotypic and genotypic diversity in the diagnosis of NM. Nemaline myopathy (NM) is a clinically heterogeneous congenital myopathy characterized by the presence of nemaline rods in the skeletal muscle fibers. We investigated the clinical variation and pathological features in Korean patients with NM. Thirteen patients were diagnosed through muscle biopsy. Six patients had the typical congenital type, which showed the motor development delay and hypotonia at birth. Six patients showed the mild childhood type with the gait disturbance. One patient had the intermediate congenital type, who needed mechanical ventilation. Regarding the distribution of weakness, five patients presented distal dominant weakness across the clinical type. High arched palates and feet deformity were observed. Equino varus deformity was identified in two patients. But, we could not find the cardiac muscle involvement. Typical nemaline rods were recognized on light microscopy with muscle biopsy from 11 patients. However, we could identify the nemaline filamentous aggregation in electro microscope (EM) from 2 patients. One of them showed a mitochondrial abnormality in EM. Type 1 fiber predominance was in all patients. The causative mutation form 8 patients was investigated, we found a missense heterozygous mutation in exon 1 of TPM3 gene (c.32T>A, p.Met11Lys). Seven patients showed negative results in ACTA1 gene. The thirteen patients in this study did not share much common feature except the dysmorphic appearance. The clinical diversity was prominent with the distribution of muscle weakness and the severity of respiratory dysfunction. This study showed the phenotypic heterogeneity of NM is not only with clinical features but also with pathological findings in our patient pool. Wider application of whole exome sequencing may help overcome the phenotypic and genotypic diversity in the diagnosis of NM.

Nebulin is a giant sarcomeric protein spanning whole length of thin filament, and its coding gene (NEB) mostly causes autosomal recessive nemaline myopathy. The NEB mutations may also cause distal nebulin myopathy with initial presentation of foot drop, and recent reports added another muscle disease of core-rod myopathy with double presentation of nemaline rods and cores. In this study, two patients with nemaline rods in muscle pathology were recruited, one of whom (patient 1) was the proband of a symptomatic sibling. Patient 1 initially presented with foot drop and has been a slow runner since childhood. His fourth elder brother also complained of foot drop and gait disturbance. Patient 2 had gait disturbance since age 5, and his ankle dorsiflexors were the most weak among all muscles. All the patients were still ambulant and never complained of respiratory restriction. Muscle CT scans revealed atrophy of anterior tibial muscles in both of patients. Muscle pathology additionally showed core lesions and mitochondrial abnormalities, as well as nemaline rods. Nemaline myopathy-causing genes were first excluded and then, whole exome sequencing and followed targeted sequencing were detected three novel mutations in NEB gene: one missense, one single bp deletion and del/ins mutations. One missense mutation was shared by all of them. This study represents the disease associated with novel NEB mutations marked by the presence of additional pathological features, as well as nemaline rods. Although mixed pathology has been already reported in core-rod myopathy with NEB mutations, muscle pathology in these patients is more characteristic, and clinical manifestation is much milder compared with the previous ones. This report suggests the expanded clinical and pathological spectrum of nebulin-associated myopathy with new genetic and pathologic features. Further, next genome sequencing might be helpful for searching mutations in big, huge-sized genes, such as NEB. Nebulin is a giant sarcomeric protein spanning whole length of thin filament, and its coding gene (NEB) mostly causes autosomal recessive nemaline myopathy. The NEB mutations may also cause distal nebulin myopathy with initial presentation of foot drop, and recent reports added another muscle disease of core-rod myopathy with double presentation of nemaline rods and cores. In this study, two patients with nemaline rods in muscle pathology were recruited, one of whom (patient 1) was the proband of a symptomatic sibling. Patient 1 initially presented with foot drop and has been a slow runner since childhood. His fourth elder brother also complained of foot drop and gait disturbance. Patient 2 had gait disturbance since age 5, and his ankle dorsiflexors were the most weak among all muscles. All the patients were still ambulant and never complained of respiratory restriction. Muscle CT scans revealed atrophy of anterior tibial muscles in both of patients. Muscle pathology additionally showed core lesions and mitochondrial abnormalities, as well as nemaline rods. Nemaline myopathy-causing genes were first excluded and then, whole exome sequencing and followed targeted sequencing were detected three novel mutations in NEB gene: one missense, one single bp deletion and del/ins mutations. One missense mutation was shared by all of them. This study represents the disease associated with novel NEB mutations marked by the presence of additional pathological features, as well as nemaline rods. Although mixed pathology has been already reported in core-rod myopathy with NEB mutations, muscle pathology in these patients is more characteristic, and clinical manifestation is much milder compared with the previous ones. This report suggests the expanded clinical and pathological spectrum of nebulin-associated myopathy with new genetic and pathologic features. Further, next genome sequencing might be helpful for searching mutations in big, huge-sized genes, such as NEB.

Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA), Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify clinical course of LOPD. In this study, we have evaluated the efficacy and adverse events of ERT for 60 weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features including motor and pulmonary function was assessed, and rhGAA was infused every two weeks. Then, patients were examined at every 12 weeks interval to evaluate their changes in motor and pulmonary function for 48 weeks along with adverse reactions of ERT. The motor and pulmonary function of the patients demonstrated mild improvement or stabilization after 60 weeks of ERT. And none of them showed deterioration in their ambulatory or respiratory status. One of our patients developed a serious anaphylactic reaction which necessitated the cessation of further ERT. This is the first report of clinical study on the ERT of Korean LOPD patients. Our study showed ERT for 48 weeks produced only mild improvement or stabilization of motor and pulmonary function in LOPD patients, suggesting that advanced pathological change is responsible for the limited efficacy of ERT. Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA), Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify clinical course of LOPD. In this study, we have evaluated the efficacy and adverse events of ERT for 60 weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features including motor and pulmonary function was assessed, and rhGAA was infused every two weeks. Then, patients were examined at every 12 weeks interval to evaluate their changes in motor and pulmonary function for 48 weeks along with adverse reactions of ERT. The motor and pulmonary function of the patients demonstrated mild improvement or stabilization after 60 weeks of ERT. And none of them showed deterioration in their ambulatory or respiratory status. One of our patients developed a serious anaphylactic reaction which necessitated the cessation of further ERT. This is the first report of clinical study on the ERT of Korean LOPD patients. Our study showed ERT for 48 weeks produced only mild improvement or stabilization of motor and pulmonary function in LOPD patients, suggesting that advanced pathological change is responsible for the limited efficacy of ERT.

Myotonia congenita is the most common non-dystrophic channelopathy of the skeletal muscle. It is characterized by clinical myotonia on voluntary contraction, accompanied by warm-up alleviation with repeated movements. Mutations of the chloride channel gene (CLCN1) are responsible for the disease. Both autosomal dominant and recessive inheritance patterns are reported, while recessive cases are more frequent. We analyzed 38 Korean patients with myotonia congenita. Twelve mutations were found and 8 of them were novel. Patch clamp recording revealed significant difference between mutated genes and WT in current density, current–voltage curve, and open probability. Noteworthy of them were 2 peculiar mutations, R47W and A298T, found together as compound heterozygotes in 6 patients. To our best knowledge, they have not been reported to cause any disease phenotype and R47W is even listed in dbSNP as minor allele. R47W is coded from exon 1 and located at N-terminal; A298T is from exon 8, the hotspot of CLCN1 mutation and reside in domain V. By electrophysiologic techniques we could successfully show the pathogenicity of CLCN1 mutations in Korean patients with myotonia congenita. Mild electrophysiological abberation of R47W may explain the paucity of its homozygous patients despite its relatively high allele frequency. However, compound heterozygosity of R47W with A298T disclosed typical electrophysiologic abnormality in myotonia congenita. Further study on heterodimeric interaction of chloride channel protein is warranted to better understand its function and abnormalities.

Background Interleukin-6 (IL-6), a proinflammatory cytokine, is thought to play a major pathological role in rheumatoid arthritis (RA). Tocilizumab is humanized anti IL-6 receptor monoclonal antibody which has been shown to improve signs and symptoms of RA. Objectives To investigate the efficacy and safety of tocilizumab in a Korean population. Methods This clinical trial was a 24-week phase III, randomized, double-blind, placebo-controlled, multicenter trial with two treatments arms and conducted from October, 2009 to October, 2010. The eligible patients had moderate to severe active RA, inadequately responding to MTX (or DMARDs). Tocilizumab at a dose of 8mg/kg or placebo were administered in a blinded manner, intravenously every 4 weeks, with stable dose of methotrexate (MTX) or other DMARDs. Results Total of 80 patients completed 24 week’s treatment with 40 patients in each treatment arm. At week 24, proportions of ACR 20, ACR 50, DAS28 remission and EULAR response were significantly higher in Tocilizumab group than in placebo group (p <0.0001, p=0.0002, p=0.0002 and p<0.0001, respectively as shown in Table 1). The mean hemoglobin level was increased and the rheumatoid factor titer was decreased in Tocilizumab group, compared to those of placebo group (p=0.0002, p=0.0055, respectively). Adverse drug reactions were more frequent in Tocilizumab group than in placebo group as follows; increased SGPT (21%), granulocytopenia (17%), leukocytopenia (15%), hypercholesterolemia (13%), pharyngitis (13%), and increased SGOT (10%). There were more incidences of serious adverse drug reactions in Tocilizumab group than in placebo group, but it was not significant (p=0.0548). Conclusions In Korean population, administration of tocilizumab 8 mg/kg in combination with MTX (with or without other DMARDs) reduced RA activity significantly. Most of RA activity parameters including ACR 20, ACR 50, DAS 28 remission and EULAR response were achieved more frequently in Tocilizumab group than in placebo group. Tocilizumab was generally well tolerated since no safety issue was observed during the study. This study was financially supported by JW Pharmaceutical Co. (KFDA clinical trial-146). References Maini RN, et al. Arthritis Rheum. 2006;54(9):2817-29. Jones G, et al. Ann Rheum Dis. 2010;69(1):88-96. Disclosure of Interest None Declared

The underlying cause of myasthenia gravis is unknown, although there is probably a genetic component to it. We sought to identify the genetic variants associated with an increased or decreased risk of developing myasthenia gravis in the Korean Multicenter MG Cohort samples. To find new genetic targets that are related to autoimmune myasthenia gravis, a whole genome-based SNP analysis was performed using an Axiom Genome-Wide ASI 1 Array plate containing 598,375 SNPs and samples from 109 MG patients and 150 neurologically normal controls. The p values of association between these SNPs and autoimmune myasthenia gravis were calculated in all the available genetic modes such as allele, dominant, recessive, and co-dominant mode using (1) MG and Control, (2) AChR-antibody positive MG and Control, (3) AChR-antibody negative MG and Control, (4) Ocular MG and Control, and (5) Generalized MG and Control samples, respectively. A total of 641 SNPs from five case–control associations showed p values of less than 0.00001. From regional analysis, we selected seven genes (RYR3, CACNA1S, SLAMF1, SOX5, FHOD3, GABRB1, SACS) for further analysis. Fatigue in MG patients was caused not only by abnormal neuromuscular transmission but also by the impairment of excitation–contraction (E–C) coupling. In the process of E–C coupling in skeletal muscle, ryanodine receptor (RyR) and dihydropyridine receptor (DHPR/CACNA1S) function as Ca2+ channels. SLAMF1 leads to IFN-α production of CD4+ T cells. IFN-α production of CD4+ T cells is associated with pathogenesis and immunoregulation of MG. However, speculating the plausibility and the biological significance of these candidate loci is premature because additional genetic data is needed to confirm the notion that these E–C coupling gene or SLAMF1 gene are associated with autoimmune MG. The present study suggests that some genetic polymorphisms might be related to autoimmune myasthenia gravis.