Yeong-Wook Song

Treating rheumatoid arthritis to target: recommendations assessment questionnaire in Korea

Treat rheumatoid arthritis (RA) to target (T2T) is an international initiative to provide the rheumatology community with clear direction on treatment targets for RA. We performed a nationwide survey in Korea among rheumatologists to measure the levels of agreement with international T2T recommendations and to assess their practical application in Korea. A questionnaire was administered to 111 physicians. Responses were assessed using a 10-point Likert scale for the level of agreement with each of 10 recommendations and a 4-point Likert scale for the degree to which each recommendation was being applied in current daily practice. Respondents were also asked whether these recommendations would result in a change in their practice. This report outlines the consensus reached for T2T in Korea and compares those results with data obtained internationally. Agreement with T2T recommendations was high with average response scores above 8.3. The majority of respondents indicated they applied the recommendations “always” and “very often” in daily practice. More than half of the participants not currently applying these recommendations were willing to change their practice, but the percentage of Korean physicians willing to change was consistently more than the international average. The results of this survey of T2T recommendations in Korean rheumatologists revealed a good correlation with the views of the international rheumatology community. These results could be utilized to define key issues for better disease control in daily practice and used as a reference to improve the treatment environment.

Genome-wide association studies identify IL23R - IL12RB2 and IL10 as Behçet's disease susceptibility loci

Behçets disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçets disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 × 10−8) and 1q32.1 (IL10, rs1554286, P = 8.0 × 10−8). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 × 10−11, odds ratio = 1.35; rs1800871 in IL10, P = 1.0 × 10−14, odds ratio = 1.45).

Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, Part 1.

Objectives To assess whether combination therapy with infliximab (IFX) plus nonsteroidal anti-inflammatory drugs (NSAIDs) is superior to NSAID monotherapy for reaching Assessment of SpondyloArthritis international Society (ASAS) partial remission in patients with early, active axial spondyloarthritis (SpA) who were naïve to NSAIDs or received a submaximal dose of NSAIDs. Methods Patients were randomised (2u2009:u20091 ratio) to receive naproxen (NPX) 1000u2005mg daily plus either IFX 5u2005mg/kg or placebo (PBO) at weeks 0, 2, 6, 12, 18 and 24. The primary efficacy measure was the percentage of patients who met ASAS partial remission criteria at week 28. Several other measures of disease activity, clinical symptoms and patient-rated outcomes were evaluated. Treatment group differences were analysed with Fisher exact tests or analysis of covariance. Results A greater percentage of patients achieved ASAS partial remission in the IFX+NPX group (61.9%; 65/105) than in the PBO+NPX group (35.3%; 18/51) at week 28 (p=0.002) and at all other visits (p<0.05, all comparisons). Results of most other disease activity and patient-reported endpoints (including Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, multiple quality of life measures and pain measures) showed greater improvement in the IFX+NPX group than the PBO+NPX group, with several measures demonstrating early and consistent improvement over 28u2005weeks of treatment. Conclusions Patients with early, active axial SpA who received IFX+NPX combination treatment were twice as likely to achieve clinical remission as patients who received NPX alone. NPX alone led to clinical remission in a third of patients.

Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study*

Objectives To evaluate the efficacy and safety of atorvastatin versus placebo in modifying lipids in patients with rheumatoid arthritis (RA) receiving the oral Janus kinase inhibitor, tofacitinib. Methods A randomised, placebo controlled, multicentre phase 2 study, open-label for tofacitinib and blinded for atorvastatin. Patients received tofacitinib 10u2005mg twice daily for 12u2005weeks; at week 6, patients were randomly assigned 1:1 to receive oral atorvastatin 10u2005mg once daily or placebo for 6u2005weeks. Main outcome measures were lipid moieties, American College of Rheumatology (ACR) response rates, disease activity score in 28 joint counts and safety. Results 111 patients meeting ACR 1987 RA criteria with active disease were enrolled. Tofacitinib-induced elevation of mean total, low-density lipoprotein (LDL) and high-density lipoprotein-cholesterol, triglycerides and apolipoprotein A-1 concentrations were sustained in placebo recipients to week 12; atorvastatin added at week 6 significantly reduced tofacitinib-associated increases in total and LDL-cholesterol, triglycerides and apolipoprotein B to below week 0 levels. Co-administration of atorvastatin resulted in a significant reduction of LDL-cholesterol versus placebo (primary endpoint; p<0.0001); from week 6 to week 12 the least squares mean reduction was 35.3% with atorvastatin, versus 5.8% increase with placebo. ACR responses were observed with tofacitinib; numerically greater rates were seen with atorvastatin versus placebo. Adverse events were consistent with phase 3 studies. Conclusions Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving tofacitinib and atorvastatin. (http://www.ClinicalTrials.gov identifier NCT01059864; Pfizer protocol A3921109).

Functional epitope of muscarinic type 3 receptor which interacts with autoantibodies from Sjögren's syndrome patients

OBJECTIVESnRecently, autoantibodies directed against muscarinic type 3 receptor (M3R) have been reported in patients with primary SS. However, the precise epitope(s) of the M3R that interacts with SS autoantibodies remains unclear. The aim of this study was to identify the functional epitope of M3R which interacts with SS immunoglobulin G (IgG).nnnMETHODSnPurified IgGs were obtained from the sera of seven SS patients (six primary and one secondary SS) and two normal persons. We examined whether SS IgG inhibits M3R function and identified the epitope using six synthetic peptides covering all the extracellular domains of M3R by microspectrofluorimetry and surface plasmon resonance-based optical biosensor system (BIAcore system).nnnRESULTSnA volume of 0.5 mg/ml SS IgG inhibited carbachol (CCh)-induced [Ca(2+)](i) transient (CICT) in human submandibular gland (HSG) cells. However, co-incubation of SS IgG with the 6th peptide (514-527 amino acid region) corresponding to the third extracellular loop of M3R, recovered CICT. The result was further confirmed by BIAcore analysis. We found that the 6th peptide interacts with IgGs from three primary SS patients in a concentration-dependent manner. The synthetic peptide which consists of amino acids 228-237 corresponding to the COOH-terminus of the second extracellular loop of M3R also bound to SS IgG. However, normal IgGs did not interact with the 6th peptide.nnnCONCLUSIONSnThe results suggest that the third extracellular loop of M3R represents a functional epitope bound by SS IgG, and thereby partly inhibits M3R function.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N=579) and African-Americans (AAs) (N=407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P<2.03 × 10−3 were observed between LN and MYH9 in EAs (N=4620), with the most pronounced association at rs2157257 (P=4.7 × 10−4, odds ratio (OR)=1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P=0.0019, OR=2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2

Objective To investigate whether biologic-free remission can be achieved in patients with early, active axial spondyloarthritis (SpA) who were in partial remission after 28u2005weeks of infliximab (IFX)+naproxen (NPX) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control. Method Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial (INFAST) Part 1 was a double-blind, randomised, controlled trial in biologic-naïve patients with early, active, moderate-to-severe axial SpA treated with either IFX 5u2005mg/kg+NPX 1000u2005mg/d or PBO+NPX 1000u2005mg/d for 28u2005weeks. Patients achieving Assessment of SpondyloArthritis international Society (ASAS) partial remission at week 28 continued to Part 2 and were randomised (1:1) to NPX or no treatment until week 52. Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests. Results At week 52, similar percentages of patients in the NPX group (47.5%, 19/40) and the no-treatment group (40.0%, 16/40) maintained partial remission, p=0.65. Median duration of partial remission was 23u2005weeks in the NPX group and 12.6u2005weeks in the no-treatment group (p=0.38). Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28, the start of follow-up treatment (NPX, 0.7; no treatment, 0.6), and remained low at week 52 (NPX, 1.2; no treatment, 1.7). Conclusions In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone, disease activity remained low, and about half of patients remained in remission during 6u2005months in which NPX was continued or all treatments were stopped.

2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups

Objective To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. Results Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) ‘probable IIM’, had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to ‘definite IIM’. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50u2009to <55% as ‘possible IIM’. Conclusions The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of ‘definite’, ‘probable’ and ‘possible’ IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Tumor necrosis factor receptor 2 polymorphism in systemic lupus erythematosus: no association with disease

Genetic factors and immune dysregulation play important roles in the development of systemic lupus erythematosus (SLE). Tumor necrosis factor receptor 2 (TNFR2) is suggested to be involved in the development of SLE because its genetic locus (1p36) encompasses one of the susceptible loci for SLE and its ligand (TNF) is associated with SLE. To investigate the role of TNFR2 in the pathogenesis of SLE, 139 Korean patients were genotyped with SLE, 137 healthy control subjects were genotyped for TNFR2 196 R/M polymorphism in exon 6 with PCR-SSCP, and the clinical characteristics of SLE were analyzed according to the genotypes. The genotype frequencies of 196 R/R, 196 R/M, and 196 M/M were 3.6%, 30.9%, and 65.5% in SLE patients and 4.4%, 26.3%, and 69.3% in healthy controls (p = 0.676). The allelic frequency of 196 R was 19.1% in SLE patients and 17.5% in healthy controls (p = 0.638, odds ratio = 1.109, and the 95% confidence interval = 0.720-1.708). The clinical characteristics were not different according to the genotypes. In conclusion, no skewed distribution of TNFR2 196 R/M polymorphism was found in Korean patients with SLE compared with healthy controls. Further studies in other populations will be needed to elucidate the role of the TNFR2 polymorphism in the development of SLE.

Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement

We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged.