Risk factors of mortality in patients with rheumatoid arthritis-associated interstitial lung disease: a single-centre prospective cohort study.

OBJECTIVES: To determine the risk factors for mortality in Korean patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) in comparison to patients with RA but without ILD (RA-nonILD). METHODS: Data were extracted from a single-centre prospective cohort of RA patients with a chest computed tomography scan at an academic referral hospital in Korea. Patients with RA-ILD enroled between May 2017 and August 2022 were selected, and those without ILD were selected as comparators. The mortality rate was calculated, and the causes of each death were investigated. We used Cox proportional hazard regression with Firth's penalised likelihood method to identify the risk factors for mortality in patients with RA-ILD. RESULTS: A total of 615 RA patients were included: 200 with ILD and 415 without ILD. In the RA-ILD group, there were 15 deaths over 540.1 person-years (PYs), resulting in mortality rate of 2.78/100 PYs. No deaths were reported in the RA-nonILD group during the 1669.9 PYs. The primary causes of death were infection (nine cases) and lung cancer (five cases), with only one death attributed to ILD aggravation. High RA activity (adjusted HR 1.87, CI 1.16-3.10), baseline diffusing capacity for carbon monoxide (DLCO) < 60% (adjusted HR 4.88, 95% CI 1.11-45.94), and usual interstitial pneumonia (UIP) pattern (adjusted HR 5.13, 95% CI 1.00-57.36) were identified as risk factors for mortality in RA-ILD patients. CONCLUSION: Patients with RA-ILD have an elevated risk of mortality compared with those without ILD. Infection-related deaths are the main causes of mortality in this population. High RA activity, low DLCO, and the UIP pattern are significantly associated with the mortality in patients with RA-ILD.

Association of HLA-DRB1 locus with treatment response to abatacept or TNF inhibitors in patients with seropositive rheumatoid arthritis.

The strongest genetic risk factor for rheumatoid arthritis (RA) has been known as HLA-DRB1 based on amino acid positions 11, 71, and 74. This study analyzed the association between specific HLA-DRB1 locus and treatment response to abatacept or TNF inhibitors (TNFi) in patients with seropositive RA. A total of 374 Korean RA patients were treated with abatacept (n = 110) or TNFi (n = 264). Associations between HLA-DRB1 and treatment response after 6 months were analyzed using multivariable logistic regression. Seropositive RA patients with HLA-DRB1 shared epitope (SE) had a favorable response to abatacept (OR = 3.67, P = 0.067) and an inversely associated response to TNFi (OR 0.57, P = 0.058) based on EULAR response criteria, but the difference was not statistically significant in comparison to those without SE. In analyses using amino acid positions of HLA-DRB1, a significant association was found between valine at amino acid position 11 of SE and good response to abatacept (OR = 6.46, P = 5.4 × 10-3). The VRA haplotype also showed a good response to abatacept (OR = 4.56, P = 0.013), but not to TNFi. Our results suggest that treatment response to abatacept or TNFi may differ depending on HLA-DRB1 locus in seropositive RA, providing valuable insights for selecting optimal therapy.

Increased risk of herpes zoster with tofacitinib treatment in Korean patients with rheumatoid arthritis: a single-center prospective study.

We aimed to determine the risk of herpes zoster (HZ) in Korean rheumatoid arthritis (RA) patients on tofacitinib compared with tumor necrosis factor inhibitor (TNFi) treatment. From the prospective cohorts of RA patients who started tofacitinib or TNFi in an academic referral hospital in Korea, patients who started tofacitinib between March 2017 and May 2021 and those who started TNFi between July 2011 and May 2021 were included. Baseline characteristics of tofacitinib and TNFi users were balanced through inverse probability of treatment weighting (IPTW) using the propensity score including age, disease activity of RA and medication use. The incidence rate of HZ in each group and incidence rate ratio (IRR) were calculated. A total of 912 patients were included: 200 tofacitinib and 712 TNFi users. There were 20 cases of HZ among tofacitinib users and 36 among TNFi users during observation period of 331.4 person-years (PYs) and 1950.7 PYs, respectively. In IPTW analysis with a balanced sample, IRR of HZ was 8.33 (95% confidence interval 3.05-22.76). Tofacitinib use increased the risk of HZ compared with TNFi in Korean patients with RA, but the rate of serious HZ or permanent discontinuation of tofacitinib due to HZ event was low.

Clinical characteristics of rheumatoid arthritis patients with interstitial lung disease: baseline data of a single-center prospective cohort.

BACKGROUND: To introduce a prospective cohort for rheumatoid arthritis (RA) patients with interstitial lung disease (ILD) and to identify their clinical features in comparison with RA patients without ILD. METHODS: Using a multidisciplinary collaborative approach, a single-center cohort for RA patients with ILD (RA-ILD) was established in May 2017, and enrolment data from May 2017 to March 2021 were used to compare the clinical features of RA patients without ILD (RA-non ILD). Multivariable logistic regression analysis was used to identify factors associated with ILD in RA patients. RESULTS: Among 148 RA-ILD and 410 RA-non ILD patients, participants in the RA-ILD group were older (65.8 ± 9.9 vs. 58.0 ± 10.4 years, P < 0.001) and included more males (35.8% vs. 14.6%, P < 0.001) than in the RA-non ILD group. The RA-ILD group had a higher proportion of late-onset RA patients (age ≥ 60 years) than in the comparator group (43.9% vs. 14.2%, P < 0.001). Multivariable logistic regression analysis showed that higher age at RA onset (OR 1.056, 95% CI 1.021-1.091), higher body mass index (BMI; OR 1.65, 95% CI 1.036-2.629), smoking history (OR 2.484, 95% CI 1.071-5.764), and oral glucocorticoid use (OR 3.562, 95% CI 2.160-5.874) were associated with ILD in RA patients, whereas methotrexate use was less likely to be associated with ILD (OR 0.253, 95% CI 0.155-0.412). CONCLUSIONS: Higher age at RA onset, smoking history, and higher BMI were associated with the presence of ILD among RA patients. Oral glucocorticoids were more frequently used whereas methotrexate was less likely to be used in RA-ILD patients.

Factors associated with selection of targeted therapy in patients with rheumatoid arthritis.

OBJECTIVE: Deciding which drug to choose for targeted therapy is an important step in sequential treatment for rheumatoid arthritis (RA). This study aimed to identify factors for selecting Janus kinase inhibitors (JAKis) rather than biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with RA in real-world practice. METHODS: We selected RA patients starting JAKis or bDMARDs from single-center prospective cohorts in Korea. Patients were divided into JAKi, tumor necrosis factor (TNF) inhibitor, and non-TNF inhibitor groups. We performed multinomial logistic regression analyses to identify factors associated with selecting JAKis. RESULTS: 145, 205, and 89 patients were included in the JAKi, TNF inhibitor, and non-TNF inhibitor groups. In multinomial regression analysis, the JAKi group was older than the TNF inhibitor group (OR 1.03, 95% confidence interval [CI] 1.01-1.05) but younger than the non-TNF inhibitor group (OR 0.97, CI 0.95-1.00). The JAKi group was less likely to have chronic pulmonary diseases compared with the TNF inhibitor group (OR 0.07, CI 0.01-0.56) or the non-TNF inhibitor group (OR 0.06, CI 0.01-0.50). Higher disease activity assessed by physician (OR 1.80, CI 1.51-2.38) and previous tacrolimus use (OR 2.05, CI 1.20-3.51) were factors suggesting selection of JAKis than TNF inhibitors. CONCLUSION: Age, pulmonary comorbidities, previous tacrolimus use, and high disease activity assessed by physician were factors influencing the selection of JAKis for RA patients in Korea.

MUC5B promoter variant rs35705950, rare but significant susceptibility locus in rheumatoid arthritis-interstitial lung disease with usual interstitial pneumonia in Asian populations.

BACKGROUND: MUC5B variant rs35705950 is the common and most significant risk variant for rheumatoid arthritis-interstitial lung disease (RA-ILD) in Western populations. However, little is known about its significant association with RA-ILD in Asian populations. We here investigate the association of rs35705950 with Korean patients with RA-ILD. METHODS: In this cross-sectional study, we genotyped rs35705950 in 2444 patients with RA. Among them, 683 patients with RA who have chest CT were divided into RA-ILD and RA-noILD. RA-ILD was classified as usual interstitial pneumonia (UIP) and other than UIP. The associations of rs35705950 with RA-ILD and its subtype were analysed using multivariable regression adjusted for age at RA diagnosis. Meta-analysis of a previously reported Japanese dataset and Korean dataset obtained for this study was conducted. RESULTS: The minor allele (T) frequency of rs35705950 was 0.37%, 1.43% and 2.38% in 2444 patients with RA, 105 patients with RA-ILD and 63 patients with UIP, respectively. Genotypic association of rs35705950 with RA-ILD was insignificant (OR 2.49, 95% CI 0.64 to 9.69, p=0.187), but showed significant association with UIP (OR 4.90, 95% CI 1.23 to 19.59, p=0.024) compared with RA-noILD. In meta-analysis (123 UIP and 878 RA-noILD) combining our data with previously reported Japanese data, this variant was found to be significantly associated with UIP (OR 3.51, 95% CI 1.19 to 10.37, p=0.023). CONCLUSION: MUC5B variant rs35705950 is a rare but significant risk factor for Asian patients with RA-ILD with UIP, suggesting a sharing of the genetic background between Asian and Western populations.

Comparative efficacy of subcutaneous (CT-P13) and intravenous infliximab in adult patients with rheumatoid arthritis: a network meta-regression of individual patient data from two randomised trials.

BACKGROUND: A subcutaneous (SC) formulation of infliximab biosimilar CT-P13 is approved in Europe for the treatment of adult patients with rheumatoid arthritis (RA). It may offer improved efficacy versus intravenous (IV) infliximab formulations. METHODS: A network meta-regression was conducted using individual patient data from two randomised trials in patients with RA, which compared CT-P13 SC with CT-P13 IV, and CT-P13 IV with reference infliximab IV. In this analysis, CT-P13 SC was compared with CT-P13 IV, reference infliximab IV and pooled data for both reference infliximab IV and CT-P13 IV. Outcomes included changes from baseline in 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI), and rates of remission, low disease activity or clinically meaningful improvement in functional disability per Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS: The two studies enrolled 949 patients with RA; pooled data for 840 and 751 patients were evaluable at weeks 30 and 54, respectively. For the CT-P13 SC versus pooled IV treatment arm comparison, differences in changes from baseline in DAS28-CRP (- 0.578; 95% confidence interval [CI] - 0.831, - 0.325; p < 0.0001), CDAI (- 3.502; 95% CI - 5.715, - 1.289; p = 0.002) and SDAI (- 4.031; 95% CI - 6.385, - 1.677; p = 0.0008) scores at 30 weeks were statistically significant in favour of CT-P13 SC. From weeks 30 to 54, the magnitude of the differences increased and remained statistically significant in favour of CT-P13 SC. Similar results were observed for the comparison of CT-P13 SC with CT-P13 IV and with reference infliximab IV. Statistically significant differences at week 30 favoured CT-P13 SC over the pooled IV treatment arms for the proportions of patients achieving EULAR-CRP good response, American College of Rheumatology (ACR) 50 and ACR70 responses, DAS28-CRP-defined remission, low disease activity (DAS28-CRP, CDAI and SDAI criteria) and clinically meaningful HAQ-DI improvement. CONCLUSIONS: CT-P13 SC was associated with greater improvements in DAS28-CRP, CDAI and SDAI scores and higher rates of clinical response, low disease activity and clinically meaningful improvement in functional disability, compared with CT-P13 IV and reference infliximab IV. TRIAL REGISTRATION: EudraCT, 2016-002125-11 , registered 1 July 2016; EudraCT 2010-018646-31 , registered 23 June 2010.

Risk of Tuberculosis Development in Patients with Rheumatoid Arthritis Receiving Targeted Therapy: a Prospective Single Center Cohort Study.

BACKGROUND: Patients with rheumatoid arthritis (RA) undergoing targeted therapy have a higher risk of developing tuberculosis (TB). This requires diagnosis and treatment of latent tuberculosis infection (LTBI). We aimed to evaluate whether diagnosis and treatment of LTBI in RA are effective in Korea, and to estimate the risk of TB development by calculating the incidence rate of active TB among RA patients receiving targeted therapy. METHODS: We analyzed data from two prospective cohort studies of RA patients who received biologic disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase (JAK) inhibitor. We selected new starters of targeted therapy and classified them into three groups receiving tumor necrosis factor (TNF) inhibitor, non-TNF inhibitor, and JAK inhibitor, respectively. We then compared LTBI prevalence, treatments, and active TB incidence during first-line therapy in each group. RESULTS: A total of 765 RA patients (574 TNF inhibitor users, 132 non-TNF inhibitor users, and 59 JAK inhibitor users) were included in this study. Observation periods were 1,255.2 person-years (PYs), 264.7 PYs, and 53.3 PYs, respectively. All 765 patients underwent LTBI screening, and the positivity rate was 26.5% (n = 203). Of the 203 LTBI-positive patients, 189 (93.1%) received treatment. Only one patient, who was in the TNF inhibitor group, and was negative for the interferon gamma release assay (IGRA), did not receive LTBI treatment and developed active TB during follow-up. CONCLUSION: Although the prevalence of LTBI in RA patients who started targeted therapy was slightly elevated, the Korean guidelines specifying LTBI screening and treatment were effective in preventing latent TB from becoming active.

Efficacy and safety of subcutaneous infliximab versus adalimumab, etanercept and intravenous infliximab in patients with rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: There are few comparative data for tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA). METHODS: Historical data for reference product/biosimilar intravenous infliximab, or adalimumab and etanercept, were pooled and compared with phase 3 study results for a subcutaneous (SC) formulation of the infliximab biosimilar CT-P13, in a systematic review and meta-analysis (PROSPERO: CRD42019149621). RESULTS: The authors identified 13 eligible controlled trials that randomized over 5400 participants to prespecified treatments of interest. Comparison with pooled historical data suggested a numerical advantage for CT-P13 SC over intravenous infliximab for almost every prespecified efficacy outcome evaluated, including Disease Activity Score in 28 joints (C-reactive protein/erythrocyte sedimentation rate), Clinical/Simplified Disease Activity Index scores, American College of Rheumatology responses, and multiple measures of disease remission and low disease activity; for the majority of outcomes, there was no overlap in 95% confidence intervals between groups. A numerical advantage for CT-P13 SC was also observed for safety outcomes (adverse events, infections, and discontinuations). Similar, but less marked, trends were observed for comparison with historical efficacy and safety data for adalimumab/etanercept. CONCLUSION: CT-P13 SC offers an improved or similar benefit-to-harm ratio compared with infliximab (intravenous) and adalimumab/etanercept, for the treatment of moderate-to-severe RA.

Autoantibodies against Protein Phosphatase Magnesium-Dependent 1A as a Biomarker for Predicting Radiographic Progression in Ankylosing Spondylitis Treated with Anti-Tumor Necrosis Factor Agents.

BACKGROUND: Patients with ankylosing spondylitis (AS) have increased levels of protein phosphatase magnesium-dependent 1A (PPM1A) and autoantibodies. We evaluated the usefulness of serum anti-PPM1A antibodies as a biomarker for AS. METHODS: Serum samples from 58 AS patients were obtained from a multicenter registry prior to the initiation of anti-TNF agents. The serum levels of anti-PPM1A antibodies were measured using ELISA. Spinal radiographic progression was defined as an increase in the modified stoke ankylosing spondylitis spinal score (mSASSS) by ≥2 units or a newly developed syndesmophyte. The role of exogenous PPM1A on bone mineralization was evaluated using primary osteoprogenitors acquired from patients with AS and non-inflammatory controls. RESULTS: The baseline levels of anti-PPM1A antibodies and mSASSS were higher in the radiographic progression group than in the non-progression group. In logistic regression analysis, baseline mSASSS and serum anti-PPM1A antibodies were associated with a higher risk of progression. The level of anti-PPM1A antibodies for predicting progression had an AUC of 0.716 (cut-off value: 43.77 ng/mL). PPM1A stimulation increased matrix mineralization in AS-osteoprogenitors but not in controls. CONCLUSION: Along with mSASSS, the serum levels of anti-PPM1A antibodies might be useful as a predictor of radiographic progression after treatment with anti-TNF agents.

Temporal relationship between idiopathic inflammatory myopathies and malignancies and its mortality: a nationwide population-based study.

OBJECTIVES: To examine the temporal relationship between malignancies and idiopathic inflammatory myopathies (IIMs) and its impact on mortality. METHODS: A retrospective cohort for IIM patients was conducted using the Korean National Health Insurance Service databases. We observed more than 5 years before and after the diagnosis of IIM (2002~2016) to identify IIM patients who developed any malignancy and classified these patients into two groups: the cancer-associated myositis (CAM) group, who developed malignancy within 3 years before or after the diagnosis of IIM and the cancer-not-associated myositis (CNAM) group, who developed malignancy beyond 3 years of IIM onset. The survival rates of the two groups were compared. RESULTS: We identified 1072 incident cases of IIM between 2007 and 2011. A total 225 patients of these patients were diagnosed with malignancy. The development of malignancy was frequent within 1 year before and after the time of IIM diagnosis. The common sites of malignancies in the CAM group differed from those in the CNAM group: the lung, hematologic malignancy, and the liver were common in both groups, but thyroid and oropharynx followed them in CAM while prostate, stomach, breast, and thyroid followed them in CNAM. CAM patient mortality was worse compared with CNAM patients (log-rank test, p < 0.01). CONCLUSIONS: Among IIM patients with malignancy, common sites of malignancy were different between the CAM and CNAM groups, and patients with CAM had poor prognosis compared with CNAM patients. Key Points • The malignancies commonly occurred in incident idiopathic inflammatory myopathy (IIM) patients, especially within 1 year before and after the initial IIM diagnosis. • Patients with malignancy had poor survival compared with patients without malignancy. • Among the IIM patients with malignancy, patients who developed malignancy within 3 years of IIM diagnosis (cancer-associated myositis, or CAM, group) showed higher mortality than cancer-not-associated myositis, CNAM group. • We also found that the common types of malignancy were different between the CAM and CNAM groups.

Increased risk of malignancy in patients aged over 50 with idiopathic inflammatory myositis compared to patients with osteoarthritis of the knee.

Objectives: To estimate risk of malignancy in patients with idiopathic inflammatory myositis (IIM) compared to patients with knee osteoarthritis (OA).Methods: Patients with IIM and knee OA aged over 50, who had no history of malignancy, were identified using Korean National claims database from January 2012 to December 2014. They had been observed until a malignancy was diagnosed or up to the end of the study, December 2015. The incidence rate (IR) of malignancy in IIM patients was calculated and compared with knee OA patients using standardized incidence ratio (SIR).Results: A total of 634 polymyositis (PM) and 556 dermatomyositis (DM) patients were included. Overall, 100 solid (IR 270.4/10,000 person-years (PY), 95% confidence interval (CI) 217.4-323.4) and 12 hematologic malignancies (IR 32.4/10,000 PY, 95% CI 14.1-50.8) occurred. Compared with knee OA, risk of overall (SIR 1.5, 95% CI 1.2-1.8), solid (SIR 1.4, 95% CI 1.1-1.6), and hematologic malignancy (SIR 5.7, 95% CI 2.5-9.0) were increased in IIM patients. This was due to increased incidence of malignancy in DM (hematologic malignancy, SIR 8.7, 95% CI 2.7-14.7, solid malignancy, SIR 1.5, 95% CI 1.1-1.9).Conclusion: Patients with IIM, especially DM, have an increased risk of malignancy compared to patients with knee OA.

An increased disease burden of autoimmune inflammatory rheumatic diseases in Korea.

OBJECTIVES: To estimate the prevalence, medical utilization, and recent changes in the economic burden of autoimmune rheumatic diseases (AIRDs) in Korea. METHODS: Using a nationwide claims database that includes all medical claims made by approximately 50 million Korean residents, the prevalences of seropositive rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and others between 2012 and 2016 were calculated. Changes in medical utilization and the direct medical costs of each AIRD from 2012 to 2016 were also evaluated. RESULTS: Based on the data for 2016, seropositive RA was the most common AIRD in Korea with 96,330 cases (188.5/100,000 population), followed by AS (30,006, 58.7/100,000 population), SLE (19,441, 38.0/100,000 population), Behçet's disease (BD, 14,943, 29.2/100,000 population), primary Sjögren syndrome (pSS, 12,018, 23.5/100,000 population), and systemic sclerosis (SSc, 3606, 7.1/100,000 population). In terms of medical utilization, patients with eosinophilic granulomatosis with polyangiitis visited outpatient clinics the most frequently (9.8 times/year/patient), while hospitalization was most frequent in microscopic polyangiitis patients (1.0 time/year/patient). Total medical costs for all AIRDs increased from $154,348,011 in 2012 to $262,481,974 in 2016. The annual medical cost per patient in 2016 was the highest in microscopic polyangiitis ($6223/year), followed by psoriatic arthritis ($3,362/year), and granulomatosis with polyangiitis ($2823/year). CONCLUSIONS: In Korea, the most prevalent AIRD is seropositive RA, followed by AS, SLE, BD, pSS, and SSc. The economic burden of AIRDs has risen substantially in the last 5 years due not only to an increase in their prevalence but also to an increase in medical costs per patient.

Safety of baricitinib in East Asian patients with moderate-to-severe active rheumatoid arthritis: An integrated analysis from clinical trials.

AIM: We evaluated the safety of baricitinib in an East Asian (EA) patient population with moderate-to-severely active rheumatoid arthritis (RA), through an integrated sub-analysis of data from the overall baricitinib RA clinical program. METHODS: Data from EA patients who received any dose of baricitinib from five completed studies (1 Phase 2, 4 Phase 3) and an ongoing long-term extension study were pooled up to 1 September, 2016. Exposure-adjusted incidence rates (EAIR) and incidence rates (IRs), both per 100 patient-years (PY), were calculated. RESULTS: This analysis included 740 EA patients with 1294 PY of total baricitinib exposure (maximum 3.5 years). Overall, 109 patients discontinued baricitinib due to adverse events (AEs); EAIR: 8.4. No deaths were reported in this cohort. Serious AEs were reported by 125 patients (EAIR: 9.7). Serious infections were the most common serious AEs (n = 53, IR: 4.15). IR of herpes zoster infection was 6.2; the majority of events were of mild-to-moderate severity. Three cases (IR: 0.23) of tuberculosis were reported. The IRs of malignancy (excluding non-melanoma skin cancer) was 0.99 and EAIR specifically of lymphoma was 0.1. The IR of major adverse cardiovascular events was 0.26, and deep vein thrombosis was reported in four patients (EAIR: 0.3). Two cases of gastrointestinal perforations (EAIR: 0.2) were reported. CONCLUSION: Integrated data show that baricitinib is well-tolerated in EA patients with moderate-to-severely active RA in the context of demonstrated efficacy, which is generally consistent with safety results of the overall study population.

Deletion at 2q14.3 is associated with worse response to TNF-α blockers in patients with rheumatoid arthritis.

BACKGROUND: Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers. METHODS: A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment. RESULTS: The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10- 5 ≤ P ≤ 4.07 × 10- 4) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK. CONCLUSIONS: This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.

Biologics for the treatment of adult-onset still's disease.

Introduction: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60-70% of patients develop a chronic form. Up to 20-30% of patients who are refractory to conventional therapy need biologic agents. Recently, anti-cytokine biologic agents according to pathophysiology have resulted in significant progress in the treatment of AOSD. Area Covered: Due to rarity and heterogeneous features of the disease, treatment of AOSD is not based on the controlled study but on case-based retrospective data. Here, we review the current status of the pathogenesis, limitations of therapeutic guidelines and outcome measures, utility of biologic agents, and future perspectives for treatment. Expert opinion: IL-1 inhibitors are more effective for systemic manifestations and IL-6 inhibitors for both joint disease and systemic features. Anti-TNF agents would be useful for patients with the pure rheumatoid subgroup. Systemic manifestations respond rapidly, but arthritis shows rather slow response. Clinical response must be obtained within 2 to 3 months, and biologics with different mechanisms of action are required for non-responders. For patients in prolonged remission, we need to try tapering of biologics. Randomized controlled studies, new therapeutic agents, and composite biomarkers are required to improve the outcome of patients with AOSD.

Isoniazid treatment for latent tuberculosis infection is tolerable for rheumatoid arthritis patients receiving tumor necrosis factor inhibitor therapy.

BACKGROUND/AIMS: To evaluate the impact of isoniazid (INH) treatment for latent tuberculosis infection (LTBI) on the development of liver function test (LFT) abnormality and the persistence of tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients. METHODS: We retrospectively enrolled patients with RA who were treated with TNF inhibitors at a university hospital between December 2000 and November 2011. After dividing the patients into two groups based on the occurrence of LFT abnormality during follow-up, we compared demographic and clinical features between the two groups. A multivariable logistic regression analysis was performed to identify the impact of INH treatment on LFT abnormality. The impact of INH treatment on the persistence of TNF inhibitors was also evaluated with the log-rank test and the Cox-proportional hazards model. RESULTS: A total of 312 RA patients including 96 patients (30.9%) who took INH for LTBI were included in this analysis. Thirty-nine patients (12.5%) experienced LFT abnormalities while using TNF inhibitors. The use of INH was associated with LFT abnormalities (odds ratio, 3.01; 95% confidence interval [CI], 1.39 to 6.48) after adjusting for covariates, including methotrexate use. However, the persistence of TNF inhibitors over 5 years did not differ between patients receiving or not receiving INH treatment (49.4 vs. 54.6%, p = 0.79). INH treatment was not a risk factor for discontinuation of TNF inhibitors (hazard ratio, 1.01; 95% CI, 0.66 to 1.57). CONCLUSION: INH treatment for LTBI in RA patients who started TNF inhibitors is associated with the occurrence of LFT abnormality; however, it does not lead to discontinuation of TNF inhibitors.

Prevalence of co-morbidities and evaluation of their monitoring in Korean patients with rheumatoid arthritis: comparison with the results of an international, cross-sectional study (COMORA).

AIM: We designed this study to evaluate the prevalence of comorbidities, their monitoring states and association with treatment medication in Korean rheumatoid arthritis (RA) patients compared with patients from other countries. METHODS: We analyzed 1050 RA patients from 11 Korean centers and compared them with 3520 patients from 16 other countries using an international, cross-sectional study evaluating comorbidities of RA (COMORA) database. RESULTS: Annual evaluations of cardiovascular (CV) risk were less frequently performed in Korea (P = 0.0011). The prevalence of CV-associated morbidity was similar between Korean and international RA patients, although the proportions of current smokers, patients with a family history of CV disease, patients with hyperlipidemia, and patients with Framingham score > 20% were significantly lower in Korea (P < 0.0001 for all), and the antiplatelet agents were more optimally used in Korea (P = 0.0004). Prostate cancer screening was less frequently performed compared to other countries (P < 0.0001). Less than 10% of Korean RA patients were given influenza and pneumococcal vaccinations according to current recommendations. CONCLUSIONS: There are differences in the prevalence of comorbidities and monitoring states of the risk factors between patients in Korea and in other countries. The prevalence of CV morbidity was similar between the two groups although the prevalence of CV risk factors was significantly low in Korea, suggesting that rheumatologists in Korea need to pay more attention to yearly CV risk monitoring, in addition to the screening of malignancy and vaccination of RA patients against infectious diseases.

Efficacy, Safety and Pharmacokinetics of Up to Two Courses of the Rituximab Biosimilar CT-P10 Versus Innovator Rituximab in Patients with Rheumatoid Arthritis: Results up to Week 72 of a Phase I Randomized Controlled Trial.

BACKGROUND: CT-P10 is a biosimilar of innovator rituximab (RTX), a biological therapy used to treat patients with rheumatoid arthritis (RA) who have responded inadequately to anti-tumor necrosis factor agents. OBJECTIVE: Our objective was to compare the clinical profile of CT-P10 versus RTX in patients with RA who received up to two courses of treatment and were followed for up to 72 weeks. METHODS: In this multicenter double-blind phase I study, patients were randomized 2:1 to receive CT-P10 1000 mg or RTX 1000 mg at weeks 0 and 2. Based on disease activity, patients could receive a second course of treatment between weeks 24 and 48. Efficacy endpoints, including mean change from baseline in Disease Activity Score using 28 joints (DAS28), safety, immunogenicity, pharmacokinetics, and pharmacodynamics were evaluated. RESULTS: In total, 154 patients were randomized to CT-P10 or RTX (n = 103 and 51, respectively); 137 (n = 92 and 45) completed the first course of treatment, of whom 83 (n = 60 and 23) were re-treated. Improvements from baseline in all efficacy endpoints were highly similar between the CT-P10 and RTX groups over both treatment courses. At week 24 after the second course, mean change from week 0 of the first course in DAS28 erythrocyte sedimentation rate was -2.47 and -2.04 for CT-P10 and RTX, respectively, (p = 0.1866) and in DAS28 C-reactive protein was -2.32 and -2.00, respectively (p = 0.3268). The proportion of patients positive for antidrug antibodies at week 24 after the second treatment course was 20.0% and 21.7% in the CT-P10 and RTX groups, respectively. The safety profile of CT-P10 was comparable to that of RTX, and pharmacokinetic and pharmacodynamic properties were similar. CONCLUSIONS: In patients with RA, efficacy, safety, and other clinical data were comparable between CT-P10 and RTX after up to two courses of treatment over 72 weeks. (ClinicalTrials.gov identifier NCT01534884).

Treatment of adult-onset still's disease: up to date.

INTRODUCTION: Adult onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60-70% of patients may develop a chronic polyphasic form of the disease or a chronic polyarthritis. Due to rarity of disease, treatment of AOSD is not based on controlled study, but on case based experiences. Areas covered: Recently, the application of anti-cytokine therapy based on pathophysiology has resulted in significant progress in the treatment of AOSD. Here, we review current knowledge of the pathogenesis, disease progression, currently available biomarkers of disease activity, standard therapeutic agents, utility of biologic agents, future perspectives for treatment and treatment of macrophage activation syndrome. Expert commentary: Accumulated clinical data suggest that chronic disease can be classified into two subsets: dominant systemic disease, and the arthritis subgroup. IL-1 inhibitors may be more efficient for systemic manifestations and IL-6 inhibitor for both joint involvement and systemic manifestations. TNF inhibitors must be reserved for patients with purely chronic articular manifestations. For ideal management of patients, it is very important to measure disease activity accurately during follow up, but no single biomarker has been classified as ideal. New therapeutic agents and composite biomarkers are needed to improve the outcome of patients with AOSD by identifying disease activity properly.