METHOD: The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database.
RESULTS: The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway.
CONCLUSION: The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.
METHODS: Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013 to 2018, were used. Predictors of lymphopenia (lymphocyte count <0.8 × 109/l) and neutropenia (neutrophil count <1.5 × 109/l) were examined using multiple failure, time-dependent survival analyses.
RESULTS: Data from 2330 patients and 18 287 visits were analysed. One thousand and eighteen patients (43.7%) had at least one episode of leucopenia; 867 patients (37.2%) had lymphopenia, observed in 3065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, AZA, MTX, tacrolimus, CYC and rituximab use. MTX and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state was negatively associated with both lymphopenia and neutropenia.
CONCLUSION: Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.
METHODS: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity.
RESULTS: Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS.
CONCLUSION: Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.
Methods: RA patients receiving standard care were enrolled consecutively from 17 sites in 11 countries from APLAR RA SIG group. Data were collected on-site by rheumatologists with a standardized case-report form. Remission was analyzed by different definitions including disease activity score using 28 joints (DAS28) based on ESR and CRP, clinical disease activity index (CDAI), simplified disease activity index (SDAI), Boolean remission definition, and clinical deep remission (CliDR). Logistic regression was used to determine related factors of remission.
Findings: A total of 2010 RA patients was included in the study, the overall remission rates were 62•3% (DAS28-CRP), 35•5% (DAS28-ESR), 30•8% (CDAI), 26•5% (SDAI), 24•7% (Boolean), and 17•1% (CliDR), respectively, and varied from countries to countries in the Asia-Pacific region. Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) prescription rate was low (17•9%). Compared to patients in non-remission, patients in remission had higher rates of b/tsDMARDs usage and lower rates of GC usage. The favorable related factors were male sex, younger age, fewer comorbidities, fewer extra-articular manifestations (EAM), and use of b/tsDMARDs, while treatment with GC was negatively related to remission.
Interpretation: Remission rates were low and varied in the Asia-Pacific region. Treatment with b/tsDMARDs and less GC usage were related to higher remission rate. There is an unmet need for RA remission in the Asia-Pacific region.
METHODS: Research questions were formulated focusing on diagnosis and treatment of adult patients with RMD within the context of the pandemic, including the management of RMD in patients who developed COVID-19. MEDLINE was searched for eligible studies to address the questions, and the APLAR COVID-19 task force convened 2 meetings through video conferencing to discuss its findings and integrate best available evidence with expert opinion. Consensus statements were finalized using the modified Delphi process.
RESULTS: Agreement was obtained around key aspects of screening for or diagnosis of COVID-19; management of patients with RMD without confirmed COVID-19; and management of patients with RMD with confirmed COVID-19. The task force achieved consensus on 25 statements covering the potential risk of acquiring COVID-19 in RMD patients, advice on RMD medication adjustment and continuation, the roles of telemedicine and vaccination, and the impact of the pandemic on quality of life and on treatment adherence.
CONCLUSIONS: Available evidence primarily from descriptive research supported new recommendations for aspects of RMD care not covered in the previous document, particularly with regard to risk factors for complicated COVID-19 in RMD patients, modifications to RMD treatment regimens in the context of the pandemic, and COVID-19 vaccination in patients with RMD.
OBJECTIVE: To evaluate the association of genetic ancestry with childhood ALL molecular subtypes and outcomes of modern ALL therapy.
DESIGN, SETTING, AND PARTICIPANTS: This multinational, multicenter genetic association study was conducted from March 1, 2000, to November 20, 2020, among 2428 children and adolescents with ALL enrolled in frontline trials from the United States, South East Asia (Singapore and Malaysia), and Latin America (Guatemala), representing diverse populations of European, African, Native American, East Asian, and South Asian descent. Statistical analysis was conducted from February 3, 2020, to April 19, 2021.
MAIN OUTCOMES AND MEASURES: Molecular subtypes of ALL and genetic ancestry were comprehensively characterized by performing RNA sequencing. Associations of genetic ancestries with ALL molecular subtypes and treatment outcomes were then evaluated.
RESULTS: Among the participants in the study, 1340 of 2318 (57.8%) were male, and the mean (SD) age was 7.8 (5.3) years. Of 21 ALL subtypes identified, 8 were associated with ancestry. East Asian ancestry was positively associated with the frequency of somatic DUX4 (odds ratio [OR], 1.30 [95% CI, 1.16-1.45]; P
OBJECTIVES: Our study intended to (i) resolve the taxonomic uncertainties between B. dorsalis and B. carambolae, (ii) reveal the population structure and global invasion routes of B. dorsalis across Asia, Africa, and Oceania, and (iii) identify genomic regions that are responsible for the thermal adaptation of B. dorsalis.
METHODS: Based on a high-quality chromosome-level reference genome assembly, we explored the population relationship using a genome-scale single nucleotide polymorphism dataset generated from the resequencing data of 487 B. dorsalis genomes and 25 B. carambolae genomes. Genome-wide association studies and silencing using RNA interference were used to identify and verify the candidate genes associated with extreme thermal stress.
RESULTS: We showed that B. dorsalis originates from the Southern India region with three independent invasion and spread routes worldwide: (i) from Northern India to Northern Southeast Asia, then to Southern Southeast Asia; (ii) from Northern India to Northern Southeast Asian, then to China and Hawaii; and (iii) from Southern India toward the African mainland, then to Madagascar, which is mainly facilitated by human activities including trade and immigration. Twenty-seven genes were identified by a genome-wide association study to be associated with 11 temperature bioclimatic variables. The Cyp6a9 gene may enhance the thermal adaptation of B. dorsalis and thus boost its invasion, which tended to be upregulated at a hardening temperature of 38 °C. Functional verification using RNA interference silencing against Cyp6a9, led to the specific decrease in Cyp6a9 expression, reducing the survival rate of dsRNA-feeding larvae exposed to extreme thermal stress of 45 °C after heat hardening treatments in B. dorsalis.
CONCLUSION: This study provides insights into the evolutionary history and genetic basis of temperature adaptation in B. dorsalis.
METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes.
RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual.
CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.
METHODS: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.
RESULTS: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).
CONCLUSION: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.
METHODS: Patients enrolled in the Asia Pacific Lupus Collaboration cohort with ≥3 years of prospectively captured data were studied. Flares were assessed at routine visits, while damage ((Systemic Lupus International Collaborating Clinics/American College of Rheumatology) Damage Index) was assessed annually. Multivariable, multifailure survival analyses were carried out to quantify the association between flares and damage accrual.
RESULTS: 1556 patients with SLE with a median (IQR) of 5.7 (3.9, 7.0) years of follow-up were studied. 39.5% (n=614) of patients had damage at enrolment, and 31.9% (n=496) accrued damage during the study observation period. The incidence of damage accrual during observation was ~58/1000 person-years. Overall, 74.1% (n=1153) of patients experienced a flare of any severity (mild/moderate or severe) at least once; 56.9% (n=885) experienced recurrent (≥2) flares. The risk of subsequent damage accrual in patients who experienced mild-to-moderate flare, after controlling for confounders, was 32% greater than in patients without flares (adjusted HR) (95% CI 1.32 (1.17 to 1.72)). The risk of damage accrual was greater if patients had severe flares (HR (95% CI) 1.58 (1.18 to 2.11)). For each additional flare, the risk of damage accrual increased by 7% (HR (95% CI) 1.07 (1.02 to 1.13)).
CONCLUSIONS: Flares independently increased the risk of damage accrual. Prevention of flares should be considered a necessary goal of SLE disease management to minimise permanent damage.
METHODS: Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded.
RESULTS: 2099 patients were included, with median follow-up of 3.5 (IQR 1.3-5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007).
CONCLUSIONS: LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares.