Safety and Effectiveness of Etanercept Biosimilar SB4 for Rheumatic Diseases in South Korea: Real-World Post-marketing Surveillance Data.

INTRODUCTION: SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea. METHODS: This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA. RESULTS: Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p < 0.0001; DAS28 3.8 vs. 5.7, p < 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893). CONCLUSION: This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals.

Sudden Onset of IgA Vasculitis Affecting Vital Organs in Adult Patients following SARS-CoV-2 Vaccines.

IgA vasculitis is an immune complex-mediated small-vessel vasculitis that mainly occurs in children and is characterized by palpable purpura, arthralgia, abdominal pain, and glomerulonephritis. We report three cases of new-onset IgA vasculitis involving major organs in adult patients after they received either the ChAdOx1 viral vector (Oxford/AstraZeneca) vaccine or the messenger RNA-1273 (Moderna) vaccine. These cases suggest that COVID-19 vaccines have the potential to trigger IgA vasculitis and indicate that physicians need to monitor for this possible complication.

Clumpy artifacts can be differentiated from tophi with DECT: comparison between gout-free and gouty patients.

OBJECTIVES: To accurately differentiate clumpy artifacts from tophi with foot and ankle DECT. METHODS AND MATERIALS: In session 1, 108 clumpy artifacts from 35 patients and 130 tophi images from 25 patients were analyzed. Reviewers classified green pixelation according to anatomic location, shape (linear, stippled, angular, oval), and height and width ratio. In session 2, green pixelation confined to the tendon was evaluated (shape, height and width ratio, occupied area in the tendon, accompanied peritendinous green pixelation). RESULTS: In session 1, while tophi were noted at various locations, almost all clumpy artifacts were located at the tendon (99%, p < 0.0001). Most clumpy artifacts were linear, stippled, and wide, while most tophi were angular and oval (p < 0.05). In session 2, the shape of green pixelation from clumpy artifacts and tophi was significantly different (p < 0.0001) and most clumpy artifacts occupied less than 50% of the tendon (p = 0.02), and most tophi were accompanied by peritendinous green pixelation (p < 0.0001). Univariant logistic regression showed that tophi were significantly correlated with peritendinous deposits, angular and oval shape, and more than 50% of the tendon (p < 0.05). CONCLUSION: Clumpy artifacts can be differentiated from tophi in DECT. Clumpy artifacts typically are located in the tendon with a linear or stippled shape, wide, and less than 50% of a tendon's cross-section. Tophi, on the other hand, typically are oval, larger than 50% of the tendon's cross-section, and associated with adjacent peritendinous green pixelation. ADVANCES IN KNOWLEDGE: Clumpy artifacts can be differentiated from tophi in image findings by their location and shape.

4-Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen-induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts.

4-Phenylbutyric acid (4-PBA) exerts potent pharmacological effects, including anti-inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4-PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4-PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)-1ß with or without 4-PBA. The effect of 4-PBA on the phosphorylation of Mitogen-activated protein kinase (MAPK) and the activation of Nuclear factor-κB (NF-κB) in IL-1ß-stimulated SFs was assessed. In an in vivo study, the effects of 4-PBA were investigated using DBA/1 mice with collagen-induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4-PBA were performed to determine the therapeutic effect of 4-PBA. In vitro, 4-PBA inhibited the proliferation and expression of IL-1ß-stimulated SFs and MMP-1 and MMP-3 through the suppression of both the phosphorylation of MAPKs and NF-κB in IL-1ß-stimulated SFs. The 4-PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4-PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP-3 and Cox-2. Furthermore, remarkable improvements in histopathological findings occurred in 4-PBA-treated mice. These findings suggested that 4-PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF-κB in SFs. Thus, through the inhibition of ER stress, 4-PBA may be a potent agent for the treatment of RA.

4-phenylbutyric acid mediates therapeutic effect in systemic lupus erythematosus: Observations in an experimental murine lupus model.

Impaired function of regulatory T cells (Tregs) contributes to the pathogenesis of systemic lupus erythematosus (SLE). Our previous study demonstrated aberrant responses of T lymphocytes to endoplasmic reticulum (ER) stress in patients with SLE. The present study investigated whether ER stress inhibition by 4-phenylbutyric acid (4-PBA) ameliorated lupus manifestations in an experimental lupus model and the effect of ER stress inhibition on the frequency and function of Tregs. A murine lupus model was induced through a 4-week treatment with Resiquimod, a toll-like receptor (TLR) 7 agonist. From the 8th week, the mice were treated with 4-PBA for 4 weeks. 4-PBA significantly decreased the levels of anti-dsDNA antibodies and serum TNF-α. A significant decrease in glomerulonephritis score was also observed in the 4-PBA-treated group. ER stress inhibition decreased the activated T and B lymphocytes population of splenocytes; however, the population of Tregs was not significantly different between the vehicle and 4-PBA group. However, a markedly enhanced suppressive capacity of Treg was detected in the 4-PBA-treated group. The present results suggest that ER stress inhibition attenuated disease activity in an experimental model by improving the suppressive capacity of Tregs. Therefore, reduction of ER stress could be used as a beneficial therapeutic strategy in SLE.

Health-related Quality of Life Outcomes of Adalimumab for Patients With Rheumatoid Arthritis in Korea.

Objective: Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disorder that impairs patients' overall health-related quality of life (HRQOL) In this study, we evaluated the effect of adalimumab in Korean patients with active RA on HRQOL. Methods: Patients included in the study had moderate to severe active RA that did not respond to conventional drugs with a Disease Activity Score of 28 joints >32 and were biologics-naïve All patients received adalimumab 40 mg subcutaneously every other week and were followed for 24 weeks The primary endpoint was the change in baseline Health Assessment Questionnaire Disability Index (HAQ-DI) score at week 24 Secondary endpoints were changes in the EuroQol 5-dimension 3-Level (EQ-5D-3L) baseline score and Short Form 36-Item Health Survey (SF-36) domain scores at weeks 12 and 24 and change in baseline HAQ-DI score at week 12. Results: In total, 91 Korean patients were included Ninety-three percent of patients were in high disease activity with a baseline mean DAS28 value of 61 within all patients The mean change from baseline in HAQ-DI scores were -046 at week 12 and∼067 at week 24 (p<00001) Additionally, EQ-5D-3L score at weeks 12 and 24 had significantly improved (p<00001) compared to baseline SF-36 at weeks 12 and 24 had significantly improved (p<00001, p=00001) compared to baseline. Conclusion: Treatment with adalimumab resulted in significant improvement in HAQ-DI, EQ-5D-3L, and SF-36 scores at 12 and 24 weeks in Korean RA patient.

Safety of Tacrolimus in Autoimmune Disease: Results From Post-marketing Surveillance in South Korea.

Objective: Tacrolimus, a macrolide immunosuppressant, is approved in Korea for the treatment of rheumatoid arthritis (RA), lupus nephritis (LN) and myasthenia gravis (MG) We report three prospective post-marketing surveillance studies of tacrolimus conducted in South Korea in these indications. Methods: Studies were conducted according to South Korean Ministry of Food and Drug Safety requirements Patients were followed up for the duration of the study (up to 4 years) or until treatment discontinuation Occurrence and likely relationship with tacrolimus of adverse events (AEs), adverse drug reactions (ADRs; defined as AEs where causal relationship to tacrolimus could not be excluded) and serious AEs were recorded Association of AEs with demographic and medical factors was evaluated by multivariable analysis. Results: The studies included 740 (RA), 307 (LN) and 104 (MG) patients The incidence of AEs was 127% in RA (642% of AEs potentially related to tacrolimus), 209% (378% potentially related) in LN and 298% (568% potentially related) in MG The incidence of ADRs was 84%, 98% and 202%, respectively Serious AEs were reported in 07%, 72% and 87%, respectively The most common AEs were abdominal pain (RA), pharyngitis (LN) and diarrhea (MG) Unexpected AEs occurred in 35% of patients with RA, 29% in LN and 87% in MG; no pattern of unexpected AEs was apparent Multivariable analysis demonstrated that patients with comorbidity had higher probability of experiencing an AE in RA and MG studies. Conclusion: The incidence of AEs and the safety profile of tacrolimus in each indication was consistent with previous reports.

Methotrexate use does not increase the prevalence of hepatic steatosis: a real-world retrospective nested case-control study.

OBJECTIVE: We aimed to determine whether methotrexate (MTX) treatment in patients with rheumatoid arthritis (RA) leads to the development of non-alcoholic fatty liver (NAFL). METHOD: Data were derived from records of all patients with RA who underwent abdominal ultrasonography at the Jeonbuk National University Hospital. Patients with ultrasound-proven NAFL were identified, and those without NAFL were matched by age and sex using the propensity score matching method at 1:3 ratio. We also analyzed the Health Insurance Review and Assessment Service-National Patient Samples, a nationwide cohort database, to determine the association between MTX use and NAFL in a large number of patients (n = 24,653). RESULTS: In the hospital cohort, 92 patients with NAFL did not show significant differences in the cumulative MTX dose when compared with the no-NAFL group (n = 276) (1908.5 ± 1757.5 vs. 1948.6 ± 2118.8 mg, p = 0.911). The prevalence of NAFL was not significantly different across strata of cumulative MTX dose. Multiple logistic analyses identified hypertriglyceridemia (OR, 4.88 [95% CI, 1.13-20.93]) and higher body mass index (OR, 1.22 [95% CI, 1.05-1.41]) as being associated with an increased risk of NAFL. In the nationwide cohort, the MTX exposure rate between the NAFL and no-NAFL groups was not significantly different. CONCLUSIONS: Collectively, no significant association between NAFL development and administration of MTX was detected in this study. Our results suggest that it is more efficient to adjust for individualized risk factors for NAFL prevention rather than discontinuation of MTX in patients with RA. Key Points • NAFLD has been highlighted with increasing prevalence worldwide and possible progression to end-stage liver disease. • Cumulative dose or exposure history of MTX does not show a significant association with NAFLD prevalence. • Modifying well-established risk factors is more efficient in NAFLD prevention rather than discontinuation of MTX.

Radiographic progression based on baseline characteristics from TNF inhibitor biosimilar studies in patients with rheumatoid arthritis.

OBJECTIVE: Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction. METHODS: Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson's correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression. RESULTS: A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson's correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001). CONCLUSIONS: In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach. CLINICAL TRIAL REGISTRATION NUMBERS: EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results.

Not All Green Is Tophi: The Importance of Optimizing Minimum Attenuation and Using a Tin Filter to Minimize Clumpy Artifacts on Foot and Ankle Dual-Energy CT.

OBJECTIVE. The clumpy artifact has a high misdiagnosis rate, but the artifact has not been well studied. The aims of this study were to evaluate the frequency and location of clumpy artifacts, the rate of misdiagnosis of clumpy artifacts as gout, and the effects of raising the minimum attenuation value and using a selective photon shield in dual-energy CT (DECT). MATERIALS AND METHODS. Forty patients without gout who underwent foot and ankle DECT were enrolled in this study. Images in both sets were randomly assigned a minimum attenuation of 130 HU or 150 HU. Three radiologists independently checked all images for presence, volume, and location of green color-coded pixelation and graded their findings according to a 4-point confidence scale, frequency, and volume. Misdiagnosis rate and misdiagnosis score were compared using the Wilcoxon signed rank and McNemar tests. RESULTS. In set 1, the frequency of clumpy artifacts in DECT with the minimum attenuation set to 130 HU and 150 HU were 81% and 68%, respectively. For all three readers, the misdiagnosis rate and misdiagnosis score decreased when changing the minimum attenuation from 130 HU to 150 HU. In set 2, with the minimum attenuation set to 130 HU, the frequency of the clumpy artifact was 44%; with the minimum attenuation set to 150 HU, no clumpy artifacts were seen. CONCLUSION. Clumpy artifacts occurred frequently in DECT without a tin filter. Setting the minimum attenuation to the higher value of 150 HU reduced the frequency of clumpy artifacts, and adding a tin filter to DECT greatly reduced their occurrence.

Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study.

BACKGROUND: To evaluate the long-term efficacy, safety and immunogenicity of continuing LBEC0101; the etanercept (ETN) biosimilar; or switching from the ETN reference product (RP) to LBEC0101 in patients with rheumatoid arthritis (RA). METHODS: This multicentre, single-arm, open-label extension study enrolled patients who had completed a 52-week randomised, double-blind, parallel phase III trial of LBEC0101 vs ETN-RP. Patients treated with ETN-RP during the randomised controlled trial switched to LBEC0101; those treated with LBEC0101 continued to receive LBEC0101 in this study. LBEC0101 (50 mg) was administered subcutaneously once per week for 48 weeks with a stable dose of methotrexate. Efficacy, safety and immunogenicity of LBEC0101 were assessed up to week 100. RESULTS: A total of 148 patients entered this extension study (70 in the maintenance group and 78 in the switch group). The 28-joint disease activity scores (DAS28)-erythrocyte sedimentation rate (ESR) were maintained in both groups from week 52 to week 100 (from 3.068 to 3.103 in the maintenance group vs. from 3.161 to 3.079 in the switch group). ACR response rates at week 100 for the maintenance vs. switch groups were 79.7% vs. 83.3% for ACR20, 65.2% vs. 66.7% for ACR50 and 44.9% vs. 42.3% for ACR70. The incidence of adverse events and the proportion of patients with newly developed antidrug antibodies were similar in the maintenance and switch groups (70.0% and 70.5%, 1.4% and 1.3%, respectively). CONCLUSIONS: Administration of LBEC0101 showed sustained efficacy and acceptable safety in patients with RA after continued therapy or after switching from ETN-RP to LBEC0101. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715908 . Registered 22 March 2016.

Treat-to-Target Strategy for Asian Patients with Early Rheumatoid Arthritis: Result of a Multicenter Trial in Korea.

BACKGROUND: To evaluate the therapeutic benefits of the treat-to-target (T2T) strategy for Asian patients with early rheumatoid arthritis (RA) in Korea. METHODS: In a 1-year, multicenter, open-label strategy trial, 346 patients with early RA were recruited from 20 institutions across Korea and stratified into 2 groups, depending on whether they were recruited by rheumatologists who have adopted the T2T strategy (T2T group) or by rheumatologists who provided usual care (non-T2T group). Data regarding demographics, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, disease activity score of 28 joints (DAS28), and Korean Health Assessment Questionnaire (KHAQ) score were obtained at baseline and after 1 year of treatment. In the T2T group, the prescription for disease-modifying antirheumatic drugs was tailored to the predefined treatment target in each patient, namely remission (DAS28 < 2.6) or low disease activity (LDA) (2.6 ≤ DAS28 < 3.2). RESULTS: Data were available for 163 T2T patients and 162 non-T2T patients. At the end of the study period, clinical outcomes were better in the T2T group than in the non-T2T group (LDA or remission, 59.5% vs. 35.8%; P < 0.001; remission, 43.6% vs. 19.8%; P < 0.001). Compared with non-T2T, T2T was also associated with higher rate of good European League Against Rheumatism response (63.0% vs. 39.8%; P < 0.001), improved KHAQ scores (-0.38 vs. -0.13; P = 0.008), and higher frequency of follow-up visits (5.0 vs. 2.0 visits/year; P < 0.001). CONCLUSION: In Asian patients with early RA, T2T improves disease activity and physical function. Setting a pre-defined treatment target in terms of DAS28 is recommended.

Infliximab biosimilar CT-P13 therapy in patients with Takayasu arteritis with low dose of glucocorticoids: a prospective single-arm study.

To evaluate the efficacy and safety of infliximab biosimilar CT-P13 in patients with active Takayasu arteritis (TAK). In this single-center open-label trial, patients with active TAK received CT-P13 at a starting dose of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks up to week 46. They were followed up until week 54. From week 14 to week 46, patients with inadequate response received increased dose of CT-P13 by 1.5 mg/kg. Concomitant prednisolone was allowed ≤ 10 mg/day. The primary efficacy end point was the achievement of partial or complete remission at week 30. All patients underwent positron emission tomography-computed tomography (PET-CT) at baseline and week 30. Twelve patients with TAK received CT-P13; one patient with protocol violation was excluded from analysis. Nine (81.8%) patients had taken concomitant prednisolone with median dose of 5.0 mg/day. At week 30, three (27.3%) patients achieved complete remission and six (54.5%) patients achieved partial remission. Statistically significant improvements in modified Indian Takayasu Clinical Activity Score (ITAS2010), ITAS-A, and serum levels of erythrocyte sedimentation rate and C-reactive protein were seen at week 30 from baseline. PET parameters were significantly reduced from baseline to week 30, including maximum standardized uptake value, target-to-vein ratio, target-to-liver ratio, and PET Vascular Activity Score. There were no serious adverse events. Treatment with CT-P13 may lead to improvement in clinical, radiographic, and serological activities with lower glucocorticoid requirement in TAK.Trial registration number NCT02457585.

Factors associated with quality of life and functional disability among rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs for at least 6 months.

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes. METHOD: A total of 2000 RA patients aged > 20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs). RESULTS: Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR < 3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR > 5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P < 0.001), and worse in females compared to males (P < 0.001). Compared to patients having lower DAS (< 3.2), those with moderate and highest DAS (3.2-5.1 and > 5.1) had worse outcome measures (P < 0.001). CONCLUSION: In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.

Panniculitis, A Rare Presentation of Onset and Exacerbation of Juvenile Dermatomyositis: A Case Report and Literature Review.

Panniculitis occurring in juvenile dermatomyositis has been rarely reported. However, it may lead to poor quality of life, and furthermore, induce an irreversible structural change in the subcutaneous layer. In this article, we present the case of a 10-year-old female patient with panniculitis that simultaneously developed with the onset and flare-up of juvenile dermatomyositis. In addition, a brief literature review of cases regarding juvenile dermatomyositis-associated panniculitis emphasizes the importance of recognizing panniculitis as a cutaneous manifestation of juvenile dermatomyositis.