Distinctive profile of monomeric and polymeric anti-SSA/Ro52 immunoglobulin A1 isoforms in saliva of patients with primary Sjögren's syndrome and Sicca.

OBJECTIVE: Primary Sjögren's syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is a disease of the salivary gland, we investigated anti-SSA/Ro52 in saliva. METHODS: Using a novel electrochemical detection platform, Electric Field-Induced Release and Measurement, we measured IgG/M/A, IgG, IgA, IgA isotypes (IgA1 and IgA2) and IgA1 subclasses (polymeric and monomeric IgA1) to anti-SSA/Ro52 in saliva supernatant of 34 pSS, 35 dry eyes and dry mouth (patients with Sicca) and 41 health controls. RESULTS: Saliva IgG/M/A, IgG, IgA, IgA isotypes and IgA1 subclasses to anti-SSA/Ro52 differed significantly between pSS, non-pSS Sicca and healthy subjects. Elevated monomeric IgA1 was observed in patients with non-pSS Sicca while elevated polymeric IgA1 (pIgA1) was observed in patients with pSS. Salivary polymeric but not monomeric IgA1 (mIgA1) isoform correlated with focus score (r2=0.467, p=0.001) CONCLUSIONS: Salivary anti-Ro52 polymeric IgA1 isoform is associated with glandular inflammation in pSS, while salivary monomeric IgA1 is associated with Sicca. Whether IgA1 isotope switching plays a role in the progression of the Sicca to pSS warrants further investigation.

Seronegative patients with primary Sjögren's syndrome and non-pSS sicca test positive for anti-SSA/Ro52 and -Ro60 in saliva.

OBJECTIVES: Testing for anti-SSA/Ro antibodies in serum is essential in the diagnostic work-up for primary Sjögren's syndrome (pSS). In this study, we aimed to validate our previous assay for detection of salivary anti-SSA/Ro52, and to develop assays for detection of salivary anti-SSA/Ro60 and for detection of anti-Ro52 and -Ro60 in plasma using the electric field-induced release and measurement (EFIRM) platform. METHODS: Whole saliva samples from two independent Danish cohorts (DN1 and DN2) including 49 patients with pSS, 73 patients with sicca symptoms, but not fulfilling the classification criteria for pSS (non-pSS sicca), and 51 healthy controls (HC), as well as plasma samples from the DN1 cohort were analyzed using EFIRM to detect anti-SSA/Ro52 and -Ro60. RESULTS: In the DN1 cohort, 100 % in the pSS group and 16 % in the non-pSS sicca group were serum anti-SSA/Ro positive by ELISA. EFIRM detected anti-SSA (Ro52 and/or -Ro60) in plasma and saliva in 100 % and 96 % patients with pSS, and 16 % and 29 % with non-pSS sicca. In the DN2 cohort, 80 % patients with pSS and 26 % with non-pSS sicca were serum anti-SSA/Ro positive. Salivary anti-SSA discriminated patients with pSS from HC and non-pSS sicca with an AUC range of 0.74-0.96 in the DN1 and DN2 cohorts. EFIRM discriminated pSS from non-pSS sicca with an AUC of 0.98 in plasma. CONCLUSION: Our findings suggest that salivary anti-SSA/Ro antibodies are potential discriminatory biomarkers for pSS, which may also identify seronegative patients, addressing the unmet clinical need of early detection and stratification of pSS.

Efficacy and safety of intravenous belimumab in a subgroup of South Korean patients with systemic lupus erythematosus enrolled into a Phase 3, randomized, placebo-controlled trial in North East Asia.

AIM: This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253). METHODS: NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores. RESULTS: Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis. CONCLUSION: Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study.

Knee osteoarthritis with a high grade of Kellgren-Lawrence score is associated with a worse frailty status, KNHANES 2010-2013.

Frailty as a syndrome of physical decline in late life is associated with adverse health outcomes. Knee osteoarthritis (KOA) could contribute to frailty conditions. The objective of this study was to evaluate the impact of KOA on frailty risk in a Korean National Health and Nutrition Examination Survey (KNHANES) cohort. In this study (N, total = 11,910, age; 64.10 years old [63.94-64.27; mean 95% CI], sex (female, %); 6,752 (56.69)), KOA patients were defined as those with knee joint pain and grade 2 Kellgren-Lawrence (K-L) or more on plain radiographic images who were 40 years old or older in Korean population data of KNHANES. The frailty index was calculated using 46 items related to co-morbidities and laboratory parameters. The impact of KOA on frailty risk was evaluated with logistic regression analyses. The prevalence of KOA patients was 35.6% [95% CI 34.7-36.46]. In polytomous logistic regression, the relative risk ratio (RRR) of KOA was significantly increased in the pre-frail group (2.76, 95% CI 2.30-3.31) and the frail group (7.28, 95% CI 5.90-8.98). RRR of frailty was significantly increased in patients with K-L grade 3 (1.36, 95% CI 1.13-1.63) and K-L grade 4 (2.19, 95% CI 1.72-2.79). Older age, higher BMI, smoking status, alcohol intake, low-income status, higher WBC count, higher platelet count, higher serum creatinine level and low estimated GFR were significantly associated with increased frailty risk. High hemoglobin and regular walking habits were associated with decreased frailty risk in KOA patients. In this large observation population- based survey cohort, KOA is linked to an increased risk of frailty syndrome. We found a significant connection between KOA and frailty syndrome. These results show that we need to think about the overall health of people with KOA and give them special care to prevent frailty syndrome.

Immunoassay Detects Salivary Anti-SSA/Ro-52 Autoantibodies in Seronegative Patients with Primary Sjögren's Syndrome.

The diagnostic work-up for Sjögren's syndrome is challenging and complex, including testing for serum autoantibodies to SSA/Ro and a labial salivary gland biopsy. Furthermore, the diagnosis is often delayed. In this study, we tested the hypothesis that anti-SSA/Ro autoantibodies are detectable in the saliva of patients with primary Sjögren's syndrome (pSS) because the disease affects the salivary glands, and these autoantibodies display greater discriminatory performance in saliva than in serum. SSA/Ro-52 Ags were used to develop what is, to our knowledge, a novel quantitative electrochemical-based immunoassay: the electric field-induced release and measurement (EFIRM) platform. The clinical utility was determined by measuring salivary anti-SSA/Ro-52 autoantibodies in patients with pSS and sicca (n = 34), patients without pSS with sicca (n = 35), and healthy subjects (n = 41). The statistical analysis of discrimination included the area under the receiver operating characteristic curve. Salivary anti-SSA/Ro-52 autoantibodies were measured in 94% (32 of 34) of patients with pSS with 85% (29 of 34) seropositivity. Four of the five seronegative patients with pSS had EFIRM-measurable anti-SSA/Ro-52 autoantibodies in saliva. Additionally, 60% (21 of 35) of the seronegative patients without pSS who had sicca had EFIRM-detectable SSA/Ro-52 autoantibodies in saliva, indicating the onset of autoimmune disease. Two of the 41 healthy control subjects had EFIRM-detectable SSA/Ro-52 autoantibodies in their saliva. Salivary SSA/Ro-52 autoantibodies significantly discriminated patients with pSS or patients with the initial stage of autoimmune disease from healthy subjects with an area under the receiver operating characteristic curve of 0.91. Our findings suggest that the proposed saliva SSA/Ro-52 immunoassay improves early and accurate diagnosis of seronegative patients with pSS and patients with early-onset autoimmune disease.

Performance of the 2016 ACR-EULAR Myositis Response Criteria in adult dermatomyositis/polymyositis therapeutic trials and consensus profiles.

OBJECTIVE: The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. METHODS: Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. RESULTS: Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. CONCLUSION: The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.

Performance of cut-offs adjusted with positive control band intensity in line-blot assays for myositis-specific antibodies.

The diagnostic performance of band intensity (BI) cut-offs, adjusted by a positive control band (PCB) in a line-blot assay (LBA) for myositis-related autoantibodies (MRAs) is investigated. Sera from 153 idiopathic inflammatory myositis (IIM) patients with available immunoprecipitation assay (IPA) data and 79 healthy controls were tested using the EUROLINE panel. Strips were evaluated for BI using the EUROLineScan software, and the coefficient of variation (CV) was calculated. Sensitivity and specificity, area under the curve (AUC), and the Youden's index (YI) were estimated at non-adjusted or PCB-adjusted cut-off values. Kappa statistics were calculated for IPA and LBA. Although inter-assay CV for PCB BI was 3.9%, CV was 12.9% in all samples, and a significant correlation was found between BIs of PCB and seven MRAs (all P < 0.05). At adjusted BI (aBI) > 10, the negative conversion rate of myositis-specific autoantibody (MSA)-positivity at BI > 10 was 11.5% in controls and 1.3% in patients. The specificity, AUC, and YI for MSAs at aBI > 10 or > 20 were higher than those at non-adjusted cut-off values. Additionally, AUC (0.720), YI (0.440), and the prevalence of MRAs with kappa > 0.60 (58.3%) were the highest at aBI > 20. The overall sensitivity and specificity for MSAs were 50.3% and 93.7% at aBI > 20, respectively, and 59.5% and 65.8% with BI > 10, respectively. The diagnostic performance of LBA can be improved using PCB-adjusted BIs. aBI > 20 is the optimal cut-off for IIM diagnosis using the EUROLINE LBA panel.

Reliability and validity of PROMIS physical function, pain interference, and fatigue as patient reported outcome measures in adult idiopathic inflammatory myopathies: International study from the OMERACT myositis working group.

OBJECTIVE: Pain interference, fatigue, and impaired physical function are common features of idiopathic inflammatory myopathies (IIM). The objective of this study was to evaluate the construct validity and test-retest reliability of the Patient Reported Outcome Information System (PROMIS) Pain Interference 6av1.0, Fatigue 7av1.0, and Physical Function 8bv2.0 instruments. METHODS: Patient-Reported Outcome Measures (PROMs) were deployed to adult IIM patients from OMERACT Myositis Working Group (MWG) international clinic sites via two online surveys (2019, 2021). Internal consistency of each PROM was analyzed by Cronbach's α. Construct validity was determined by a priori hypotheses generated by the MWG with >75% agreement for each hypothesis and calculated with Pearson correlations. Test-retest reliability was assessed using intraclass correlation coefficient with PROMIS instruments administered at time zero and 7 days. RESULTS: Surveys were sent to 368 participants in total; participants who completed each questionnaire varied (n=65 to 263). For construct validity, 10 out of 13 a priori hypotheses were met supporting construct validity of PROMIS instruments (Pain Interference 3/4, fatigue 4/4, and Physical Function 3/5). Test-retest reliability was strong for all PROMIS instruments. All PROMIS instruments demonstrated excellent internal consistency. None of the measures demonstrated any ceiling or floor effects except for a ceiling effect in the Pain Interference instrument. CONCLUSIONS: This study presents test-retest reliability and construct validity evidence supporting PROMIS Pain Interference (6a v1.0), Fatigue (7a v1.0), and Physical Function (8b v2.0) using a large international cohort of patients with IIM. Internal consistency of these instruments was excellent. A ceiling effect was noted in the Pain Interference instrument.

Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients.

OBJECTIVES: Behçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease. METHODS: A total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients. RESULTS: Genetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10-7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients. CONCLUSIONS: Male patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease.

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis.

Extracellular PKM2 (exPKM2) levels have been reported to be increased in several cancers and inflammatory diseases, including rheumatoid arthritis (RA). This study aimed to investigate the association of circulating exPKM2 levels with radiographic progression in RA patients and the effect of exPKM2 on osteoclastogenesis. Plasma and synovial fluid exPKM2 levels were significantly elevated in RA patients. Plasma exPKM2 levels were correlated with RA disease activity and were an independent predictor for radiographic progression in RA patients with a disease duration of ≤ 12 months. CD14+ monocytes but not RA fibroblast-like synoviocytes secreted PKM2 upon stimulation with inflammatory mediators. Recombinant PKM2 (rPKM2) increased the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and resorption pit in osteoclast precursors, dose-dependently, even in the absence of receptor activator of nuclear factor-kappa B ligand (RANKL). rPKM2 treatment upregulated the expression of dendrocyte-expressed seven transmembrane protein (DC-STAMP) and MMP-9 via the ERK pathway. Although rPKM2 did not directly bind to RAW264.7 cells, extracellular application of pyruvate, the end-product of PKM2, showed effects similar to those seen in rPKM2-induced osteoclastogenesis. These results suggest that exPKM2 is a potential regulator of RA-related joint damage and a novel biomarker for subsequent radiographic progression in patients with early-stage RA.

The effect of 24-week belimumab treatment withdrawal followed by treatment restart in patients with SLE: an open-label, non-randomised 52-week study.

BACKGROUND: Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE. METHODS: This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed. RESULTS: The primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals. CONCLUSIONS: Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02119156 . Registered on April 21, 2014.

Evaluation of Serum Matrix Metalloproteinase-3 as an Objective Indicator for the Disease Activity in Rheumatoid Arthritis Patients Treated With Methotrexate Versus Tocilizumab: 24-week Results From a Prospective Randomized Controlled Study.

Objective: This study aims to evaluate the change in serum metalloproteinase-3 (MMP-3) following the management of active rheumatoid arthritis (RA) and define the relationships between MMP-3 and disease activity indices. Methods: Data from a previously reported a 24-week, randomized controlled trial to investigate efficacy of tocilizumab in active RA refractory to methotrexate were analyzed. The serum level of MMP-3 were measured at week 0, 12, 20, and 24. The changes in MMP-3, and the relationship between MMP-3 and clinical parameters was assessed based on treatment group, methotrexate with or without tocilizumab. Results: A total of 95 patients were included in this study. The serum MMP-3 significantly decreased and showed similar pattern with other disease activity indices during treatment period in both treatment groups (p<0.001). The MMP-3 was positively correlated with ESR, CRP, DAS28, SDAI, and CDAI for 302 visits throughout 24 weeks (p<0.001). In another correlation analysis to evaluate the treatment effect at 24 week time point, methotrexate group showed significant correlation between serum markers MMP-3 (r=0.321, p=0.043); ESR (r=0.450, p=0.002); and CRP (r=0.536, p<0.001), with DAS28, but tocilizumab group didn't show meaningful correlation between serum markers and DAS28 (p>0.05). Conclusion: Serum MMP-3 showed positive correlation with disease activity indices in active RA patients. Furthermore, serum MMP-3 significantly decreased from baseline to week 20. As there is no single serum marker that can represent the disease activity particularly in tocilizumab treatment, MMP-3 might be a useful adjunct indicator to evaluate the treatment response in active RA patients.

Isolated Tuberculous Myositis: A Systematic Review and Multicenter Cases.

Objective: To investigate the clinical features and associated underlying conditions of isolated tuberculous myositis (ITBM), a rare extrapulmonary tuberculosis (TB). Methods: A systematic literature search and a multicenter survey were performed using a triangulation strategy. Data from the identified ITBM cases were extracted and analyzed to determine the underlying conditions, clinical presentations, treatments, and outcomes. Results: Based on the systematic review, we identified 58 ITBM, including 9 pediatric, cases in the literature published from 1981 to 2021 25 (43.1%) immunocompromised and 33 (56.9%) non-immunocompromised patients. Immunocompromised cases had a significant shorter symptom duration (median 30.0 vs. 75.0 days) and a higher prevalence of multilocular involvement (20.8% vs. 0%). Among 24 immunocompromised adult patients, dermatomyositis/polymyositis (DM/PM; n=10, 41.7%) were the most common underlying diseases in adults with ITBM identified in the systematic review. Over the past 20 years, 11 Korean adults with ITBM were identified in the multicenter survey. Of 7 immunocompromised cases, two (28.6%) were DM/PM patients. TB death rate of immunocompromised patients was 0.0% and 5/23 (21.7%) in the pediatric and adult ITBM cases identified in the systematic review, respectively, and 3/7 (42.9%) in survey-identified ITBM cases. Conclusion: ITBM has a unique clinical presentation including fever, tenderness, local swelling, overlying erythema, abscess formation and was associated with a grave outcome, especially in immunocompromised hosts. DM/PM was a highly prevalent underlying disease in both systematic review-identified and survey-identified immunocompromised ITBM patients.

Two-year clinical outcomes after discontinuation of long-term golimumab therapy in Korean patients with rheumatoid arthritis.

BACKGROUND/AIMS: The aim of this study was to investigate long-term post-discontinuation outcomes in patients with rheumatoid arthritis (RA) who had been treated with tumor necrosis factor-α inhibitors (TNF-αi) which was then discontinued. METHODS: Sixty Korean patients with RA who participated in a 5-year GO-BEFORE and GO-FORWARD extension trials were included in this retrospective study. Golimumab was deliberately discontinued after the extension study (baseline). Patients were then followed by their rheumatologists. We reviewed their medical records for 2 years (max 28 months) following golimumab discontinuation. Patients were divided into a maintained benefit (MB) group and a loss-of-benefit (LB) group based on treatment pattern after golimumab discontinuation. The LB group included patients whose conventional disease-modifying antirheumatic drug(s) were stepped-up or added/switched (SC) and those who restarted biologic therapy (RB). RESULTS: The mean age of patients at baseline was 56.5 years and 55 (91.7%) were females. At the end of follow-up, 23 (38.3%) patients remained in the MB group. In the LB group, 75.7% and 24.3% were assigned into SC and RB subgroups, respectively. Fifty percent of patients lost MB after 23.3 months. Demographics and clinical variables at baseline were comparable between MB and LB groups except for age, C-reactive protein level, and corticosteroid use. Restarting biologic therapy was associated with swollen joint count (adjusted hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.01 to 3.55) and disease duration (adjusted HR, 1.12; 95% CI, 1.02 to 1.23) at baseline. CONCLUSION: Treatment strategies after discontinuing TNF-αi are needed to better maintain disease control and quality of life of patients with RA.

Comparison of the efficacy and safety of LBAL, a candidate adalimumab biosimilar, and adalimumab reference product in patients with active rheumatoid arthritis inadequately responding to methotrexate: a 52-week phase III randomised study.

OBJECTIVES: To evaluate the similarities between LBAL (adalimumab biosimilar candidate) and the adalimumab reference product (ADL) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 56-week study was conducted in Japan and Korea. During the first 24 weeks, patients subcutaneously received 40 mg of LBAL or ADL every two weeks (LBAL and ADL groups). During the subsequent 28 weeks, the LBAL group patients and half of the ADL group patients received LBAL (L-L and A-L arms). The remaining ADL group patients continued to receive ADL (A-A arm). The primary efficacy endpoint was the change from baseline in disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) at Week 24. American College of Rheumatology (ACR) response rates, adverse events (AEs), and anti-drug antibody (ADA) were also assessed. RESULTS: In total, 383 patients were randomised. The least squares (LS) mean changes from baseline in DAS28-ESR at Week 24 were -2.45 and -2.53 in the LBAL (n=191) and ADL (n=190) groups, respectively. The 95% confidence interval (CI; -0.139, 0.304) of the difference (0.08) was within the pre-specified equivalence margin (-0.6, 0.6). Up to Week 52, the decreases in DAS28-ESR were maintained in all three arms. No notable differences in ACR20/50/70 were observed. The AE and ADA incidences were comparable between the arms. CONCLUSIONS: LBAL was equivalent in efficacy and comparable in safety, including immunogenicity, to ADL. Switching from ADL to LBAL did not impact on efficacy and safety.

All-cause and cause-specific mortality of patients with rheumatoid arthritis in Korea: A nation-wide population-based study.

OBJECTIVE: To compare all-cause and cause-specific mortality between rheumatoid arthritis (RA) patients versus the general population of Korea. METHODS: A nationally representative RA population aged≥40 years was identified from Korea National Health Insurance Service (KNHIS) database. We estimated age- and sex-adjusted all-cause and cause-specific standardized mortality ratios (SMRs) with 95% confidence intervals (CIs), comparing RA patients to the general population. Subgroup analyses were done by sex, age group, calendar year, and biologics use. RESULTS: We identified 79,352 RA patients with 6404 deaths during 2011-2016. The all-cause SMR [95% CI] of RA patients compared to the general population was 1.53 [1.49-1.56]. The top five causes of death were cancer (19.5%), respiratory disease (19.1%), cardiovascular disease (18.8%), systemic rheumatic diseases (9.5%, 9.1% due to RA), and infection (6.1%). Cause-specific SMRs [95% CI] were 0.95 [0.90-1.01] for cancer, 3.34 [3.15-3.52] for respiratory disease, 1.26 [1.18-1.33] for cardiovascular disease, 3.41 [3.08-3.75] for infection, and 4.88 [3.10-6.65] for non-RA systemic rheumatic disease. The SMR of RA population was slightly higher among men than women, and highest in their 60s and 70s. The yearly SMR increased from 1.10 [1.01-1.18] in 2011 to 1.85 [1.75-1.95] in 2016 due to population aging and comorbidity accumulation. Users of biologics showed a higher SMR than non-users (1.82 [1.69-1.96] vs. 1.50 [1.46-1.54]), due to higher RA activity, and more comorbidities despite a younger mean age. CONCLUSION: RA patients in Korea experienced 1.5-fold increase in all-cause mortality compared to the general population. Except for cancer, the top five causes of death were associated with excess mortality among RA patients. RA-associated mortality was largely determined by age, RA activity, and comorbidity status.

Impact of Infliximab Biosimilar CT-P13 Dose and Infusion Interval on Real-World Drug Survival and Effectiveness in Patients with Ankylosing Spondylitis.

CT-P13 is an infliximab biosimilar approved for indications including ankylosing spondylitis (AS); the approved maintenance regimen is 5 mg/kg infused every 6-8 weeks. In clinical practice, modifications to infliximab dose and/or infusion interval can be beneficial to the patient. For CT-P13, real-world data on dose and/or interval adjustment are lacking. This analysis investigated the impact of such treatment pattern changes on effectiveness and drug survival up to five years for adult (≥18 years old) patients with AS in the Korean, real-world, retrospective rheumatoid arthritis and ankylosing spondylitis (RAAS) study. Overall, 337 patients with AS were identified: 219 who initiated infliximab treatment with CT-P13 ('naïve') and 118 who switched from reference infliximab to CT-P13 ('switched'). Overall, 18/235 (7.7%), 110/224 (49.1%), and 101/186 (54.3%) evaluable patients had dose, infusion interval, or combined treatment pattern changes, respectively. More naïve (61.0%) versus switched (42.6%) patients had treatment pattern changes. Overall, Bath Ankylosing Spondylitis Disease Activity Index scores decreased from baseline to week 54, then remained stable; improvements were greater for patients with than without treatment pattern changes. Drug survival did not differ significantly between patients with or without treatment pattern changes. Findings suggest that adjusting dose and/or infusion interval can improve clinical outcomes for CT-P13-treated patients with AS.

CCL3L3-null status is associated with susceptibility to systemic lupus erythematosus.

The correlation between copy number variation (CNV) and the susceptibility to systemic lupus erythematosus (SLE) has been reported for various immunity-related genes. However, the contribution of CNVs to SLE susceptibility awaits more investigation. To evaluate the copy numbers in immunity-related genes such as TNFAIP3, TNIP1, IL12B, TBX21 (T-bet), TLR7, C4A, C4B, CCL3L1, and CCL3L3, the modified real competitive polymerase chain reaction (mrcPCR) assay was employed, and the association between the copy numbers and SLE susceptibility was analyzed in 334 SLE patients and 338 controls. CCL3L3-null status was significantly associated with SLE susceptibility (OR > 18, P < 0.0001), which remained significant by Bonferroni's correction (corrected P = 0.0007). However, the significant association between C4B low-copy status and SLE susceptibility (OR = 1.6051, P = 0.0331) became non-significant by Bonferroni's correction (corrected P = 0.3938). Except for these results, no other significant association between SLE susceptibility and copy number status in other genes was observed. The CCL3L3-null status may be a significant factor for SLE susceptibility.

Association of retroperitoneal fibrosis with malignancy and its outcomes.

INTRODUCTION: Retroperitoneal fibrosis (RPF) is characterized by a highly fibrotic retroperitoneal mass and encompasses the idiopathic form and secondary to malignancies. Because we have limited knowledge whether RPF is associated with malignancy, we aimed to investigate the relationship between RPF and malignancy and to compare the characteristics and prognosis of cancers among patients with RPF. METHODS: Medical records of 111 patients diagnosed as having RPF were reviewed and 38 cases of cancer, confirmed by biopsy, were identified. Standardized incidence ratios (SIRs) were calculated for cancers and stratified according to cancer type and RPF-cancer diagnosis interval. Cancer characteristics and outcomes were compared between RPF-cancer diagnosis intervals. RESULTS: The average age at RPF diagnosis was 59.2 ± 15.0 years, and 69.4% of the patients were male. The cancer SIRs in patients with RPF relative to age- and sex-matched individuals in the general population was 2.2 (1.6-3.1). SIRs of renal pelvis cancer and multiple myeloma were significantly higher than in the general population. When stratified by RPF-cancer intervals, the SIR for cancer was 9.9 within 1 year of RPF diagnosis, while no significant increase in the SIR was found after 1 year from RPF diagnosis. Cancer stage was more advanced at the time of diagnosis in patients within a 1-year interval for RPF than those with cancer within a >5-year interval, with a correspondingly increased mortality in the former patients. CONCLUSIONS: RPF was significantly associated with malignancy, particularly those diagnosed within 1 year of RPF diagnosis. Cancer stages at diagnosis were more advanced and the mortality rate was higher in patients within a 1-year interval between RPF and cancer diagnosis than in those with a >5-year interval between diagnoses.