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Objective: High disease activity status (HDAS) in patients with systemic lupus erythematosus (SLE) is associated with adverse long-term outcomes. We examined the frequency of lupus low disease activity state (LLDAS) and remission (REM) attainment in HDAS patients and whether their attainment was associated with improved patient outcomes., Methods: Demographic, clinical and outcomes data, collected prospectively from a multinational cohort between 2013 and 2020, were analysed. Disease activity was assessed using SLEDAI-2K. HDAS was defined as SLEDAI-2K ≥ 10. Patients' first visit with SLEDAI-2K ≥ 10 was assigned as baseline. Survival analyses were performed to examine the associations between cumulative and sustained LLDAS and REM attainment in HDAS patients and subsequent organ damage accrual and flare., Results: 1,029 HDAS patients with a median study duration of 2.7 years [IQR: 1.0, 4.8] were studied. LLDAS and REM were attained at least once by 71% (LLDAS-ever, n = 726) and 41% (REM-ever, n = 418) of patients. Approximately one-fifth of patients attained ≥50% cumulative time in LLDAS or REM. 37% (n = 385) of patients attained ≥3months of sustained LLDAS, with progressively lower proportions of patients attaining longer periods of sustained LLDAS. Lower proportions of patients attained sustained REM. Attainment of cumulative and sustained LLDAS or REM provided significant protection against damage accrual and flare in HDAS patients. Sustained periods of LLDAS and REM were difficult to achieve and therefore a more stringent target, but provided the most protection against damage accrual or flare., Conclusion: LLDAS and REM were achievable targets in HDAS patients, and provided significant protection against adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Lupus remains a disease with a low prioritisation in the national agendas of many countries in Latin America, the Middle East, and Asia-Pacific, where there is a dearth of rheumatologists and limited access to new or even standard lupus treatments. There is thus an important need for education, advocacy, and outreach to prioritise lupus in these regions to ensure that patients receive the care they need. This article reviews some of the specific challenges facing the care and management of people with lupus in these regions and suggests strategies for improving patient outcomes. Specifically, we review and discuss (with a focus on the aforementioned regions) the epidemiology of lupus; economic costs, disease burden, and effects on quality of life; barriers to care related to disease assessment; barriers to effective treatment, including limitations of standard treatments, high glucocorticoid use, inadequate access to new treatments, and low adherence to medications; and strategies to improve lupus management and patient outcomes. We hope that this represents a call to action to come together and act now for the lupus community, policymakers, health authorities, and healthcare professionals to improve lupus management and patient outcomes in Latin America, the Middle East, and Asia-Pacific., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objective: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive., Methods: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare., Results: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009)., Conclusion: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Evidence on long-term associations between coronavirus disease 2019 (COVID-19) and risks of multi-organ complications and mortality in older population is limited. This study evaluates these associations., Research Design and Methods: The cohorts included patients aged ≥60 year diagnosed with COVID-19 infection (cases), between 16 March 2020 and 31 May 2021 from the UK Biobank; and between 01 April 2020 and 31 May 2022 from the electronic health records in Hong Kong. Each patient was randomly matched with individuals without COVID-19 infection based on year of birth and sex and were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK cohort. Patients with COVID-19 infection over 6 months after the date of last dose of vaccination and their corresponding controls were excluded from our study. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. For evaluating long-term association of COVID-19 with multi-organ disease complications and mortality after 21-days of diagnosis, Cox regression was employed., Result: 10,759 (UKB) and 165,259 (HK) older adults with COVID-19 infection with matched 291,077 (UKB) and 1,100,394 (HK) non-COVID-19-diagnosed older adults were recruited. Older adults with COVID-19 were associated with a significantly higher risk of cardiovascular outcomes [major cardiovascular disease (stroke, heart failure and coronary heart disease): hazard ratio(UKB): 1.4 (95% Confidence interval: 1.1,1.6), HK:1.2 (95% CI: 1.1,1.3)]; myocardial infarction: HR(UKB): 1.8 (95% CI: 1.3,2.4), HK:1.2 (95% CI: 1.0,1.4)]; respiratory outcomes [interstitial lung disease: HR(UKB: 3.4 (95% CI: 2.5,4.5), HK: 4.0 (95% CI: 1.3,12.8); chronic pulmonary disease: HR(UKB): 1.7 (95% CI: 1.3,2.2), HK:1.6 (95% CI: 1.3,2.1)]; neuropsychiatric outcomes [seizure: HR(UKB): 2.6 (95% CI: 1.7,4.1), HK: 1.6 (95% CI: 1.2,2.1)]; and renal outcomes [acute kidney disease: HR(UKB): 1.4 (95% CI: 1.1,1.6), HK:1.6 (95% CI: 1.3,2.1)]; and all-cause mortality [HR(UKB): 4.9 (95% CI: 4.4,5.4), HK:2.5 (95% CI: 2.5,2.6)]., Conclusion: COVID-19 is associated with long-term risks of multi-organ complications in older adults (aged ≥ 60). Infected patients in this age-group may benefit from appropriate monitoring of signs/symptoms for developing these complications., (© International Society of Travel Medicine 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Phase separation underpins many biologically important cellular events such as RNA metabolism, signaling, and CO2 fixation. However, determining the composition of a phase-separated organelle is often challenging due to its sensitivity to environmental conditions, which limits the application of traditional proteomic techniques like organellar purification or affinity purification mass spectrometry to understand their composition. In Chlamydomonas reinhardtii, Rubisco is condensed into a crucial phase-separated organelle called the pyrenoid that improves photosynthetic performance by supplying Rubisco with elevated concentrations of CO2. Here, we developed a TurboID-based proximity labeling technique in which proximal proteins in Chlamydomonas chloroplasts are labeled by biotin radicals generated from the TurboID-tagged protein. By fusing 2 core pyrenoid components with the TurboID tag, we generated a high-confidence pyrenoid proxiome that contains most known pyrenoid proteins, in addition to new pyrenoid candidates. Fluorescence protein tagging of 7 previously uncharacterized TurboID-identified proteins showed that 6 localized to a range of subpyrenoid regions. The resulting proxiome also suggests new secondary functions for the pyrenoid in RNA-associated processes and redox-sensitive iron-sulfur cluster metabolism. This developed pipeline can be used to investigate a broad range of biological processes in Chlamydomonas, especially at a temporally resolved suborganellar resolution., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: Observable symptoms of Bell's palsy following vaccinations arouse concern over the safety profiles of novel coronavirus disease 2019 (COVID-19) vaccines. However, there are only inconclusive findings on Bell's palsy following messenger (mRNA) COVID-19 vaccination. This study aims to update the previous analyses on the risk of Bell's palsy following mRNA (BNT162b2) COVID-19 vaccination., Methods: This study included cases aged ≥16 years with a new diagnosis of Bell's palsy within 28 days after BNT162b2 vaccinations from the population-based electronic health records in Hong Kong. Nested case-control and self-controlled case series (SCCS) analyses were used, where the association between Bell's palsy and BNT162b2 was evaluated using conditional logistic and Poisson regression, respectively., Results: Totally 54 individuals were newly diagnosed with Bell's palsy after BNT162b2 vaccinations. The incidence of Bell's palsy was 1.58 (95% confidence interval [CI], 1.19-2.07) per 100 000 doses administered. The nested case-control analysis showed significant association between BNT162b2 vaccinations and Bell's palsy (adjusted odds ratio [aOR], 1.543; 95% CI, 1.123-2.121), with up to 1.112 excess events per 100 000 people who received 2 doses of BNT162b2. An increased risk of Bell's palsy was observed during the first 14 days after the second dose of BNT162b2 in both nested case-control (aOR, 2.325; 95% CI, 1.414-3.821) and SCCS analysis (adjusted incidence rate ratio, 2.44; 95% CI, 1.32-4.50)., Conclusions: There was an overall increased risk of Bell's palsy following BNT162b2 vaccination, particularly within the first 14 days after the second dose, but the absolute risk was very low., Competing Interests: Potential conflicts of interest. E. Y. F. W. has received research grants from the Food and Health Bureau of the Government of the HKSAR and the Hong Kong Research Grants Council (RGC), outside the submitted work. C. S. L. C. has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong RGC, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, and Amgen (all paid to institution) and a personal fee from Primevigilance Ltd, outside the submitted work. E. W. Y. C. reports honorarium from the Hospital Authority and grants from the Hong Kong RGC, Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Wellcome Trust, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, and the Narcotics Division of the Security Bureau of HKSAR, outside the submitted work (no payments from Wellcome Trust, all other payments to institution). F. T. T. L. has been supported by the RGC Postdoctoral Fellowship under the Hong Kong RGC (paid to institution Chinese University of Hong Kong) and has received research grants from the Food and Health Bureau of the Government of the HKSAR, outside the submitted work. X. L. has received research grants from the Food and Health Bureau of the Government of the HKSAR, RGC Early Career Scheme, and RGC Research Matching Grant Scheme; research and educational grants from Janssen and Pfizer (all paid to institution); internal funding from the University of Hong Kong; a consultancy fee from Merck Sharp & Dohme, paid to author and unrelated to this work; and payment to author for lectures, presentations, speakers bureaus, manuscript writing, and educational events from Pfizer. K. K. L. received grants from the Research Fund Secretariat of the Food and Health Bureau, Innovation and Technology Bureau, RGC, Amgen, Boehringer Ingelheim, Eisai, and Pfizer and consultation fees from Amgen, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, all outside the submitted work. B. J. C. received consulting fees paid to author from AstraZeneca, Fosun Pharma, GSK, Moderna, Pfizer, Roche, and Sanofi Pasteur. I. F. N. H. received speaker fees from MSD for the COVID-19 Regional Expert Input Forum 2021 and Herpes Zoster Lecture 2021. I. C. K. W. reports research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong RGC, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, Narcotics Division of the Security Bureau of HKSAR, and the Wellcome Trust; received speaker fees paid to author from Janssen, Medice, and Amgen; and is an independent nonexecutive director of Jacobson Medical in Hong Kong. C. K. H. W. has received grants or contracts paid to institution from Health and Medical Research Fund, Food and Health Bureau, HKSAR Government, General Research Fund, RGC, HKSAR Government, and Euroqol Research Foundation. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Early antiviral therapy was effective in the treatment of coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of combined interferon beta-1b and remdesivir treatment in hospitalized COVID-19 patients., Methods: We conducted a multicentre, prospective open-label, randomized-controlled trial involving high-risk adults hospitalized for COVID-19. Patients were randomly assigned to a 5-day interferon beta-1b 16 million units daily and remdesivir 200 mg loading on day 1 followed by 100 mg daily on day 2 to 5 (combination group), or to remdesivir only of similar regimen (control group) (1:1). The primary endpoint was the time to complete alleviation of symptoms (NEWS2 = 0)., Results: Two-hundred and twelve patients were enrolled. The median days of starting treatment from symptom onset was 3 days. The median age was 65 years, and 159 patients (75%) had chronic disease. The baseline demographics were similar. There was no mortality. For the primary endpoint, the combination group was significantly quicker to NEWS2 = 0 (4 vs 6.5 days; hazard ratio [HR], 6.59; 95% confidence interval [CI], 6.1-7.09; P < .0001) when compared to the control group. For the secondary endpoints, the combination group was quicker to negative nasopharyngeal swab (NPS) viral load (VL) (6 vs 8 days; HR, 8.16; 95% CI, 7.79-8.52; P < .0001) and to develop seropositive immunoglobulin G (IgG) (8 vs 10 days; HR, 10.78; 95% CI, 9.98-11.58; P < .0001). All adverse events resolved upon follow-up. Combination group (HR, 4.1 95% CI, 1.9-8.6, P < .0001) was the most significant independent factor associated with NEWS2 = 0 on day 4., Conclusions: Early treatment with interferon beta-1b and remdesivir was safe and better than remdesivir only in alleviating symptoms, and in shortening viral shedding and hospitalization with earlier seropositivity in high-risk COVID-19 patients., Clinical Trials Registration: NCT04647695., Competing Interests: Potential conflicts of interest. I. F. H received honoraria as speaker from MSD for COVID-19 Regional Expert Input Forum 2021 and Herpes Zoster lecture 2021 and was a member of the Advisory Board for Pfizer on COVID-19 Management 2022 and Gilead on Evolving Treatment Landscape in COVID-19 2021. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis associated with a number of extra-articular manifestations. We report the case of a rare extra-articular manifestation of seropositive RA in a 48-year-old woman. She developed spontaneously remitting pustular rashes on the dorsum of both hands which recurred during periods of a high disease activity. Skin biopsy revealed rheumatoid neutrophilic dermatosis (RND), a rare skin manifestation of RA. Both RA and RND were controlled with rituximab therapy. Clinical presentations and differential diagnoses were discussed. Tight control of RA is pivotal in the management of RA and extra-articular manifestations., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In view of limited evidence that specifically addresses vaccine effectiveness (VE) in the older population, this study aims to evaluate the real-world effectiveness of BNT162b2 and CoronaVac in older adults during the Omicron BA.2 outbreak., Methods: This case-control study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Each case was matched with up to 10 controls by age, sex, index date and Charlson Comorbidity Index for the four outcomes (COVID-19 infection, COVID-19-related hospitalization, severe complications, and all-cause mortality) independently. Conditional logistic regression was conducted to evaluate VE of BNT162b2 and CoronaVac against COVID-19-related outcomes within 28 days after COVID-19 infection among participants stratified by age groups (60-79, ≥80 years old)., Results: A dose-response relationship between the number of vaccine doses received and protection against severe or fatal disease was observed. Highest VE (95% CI) against COVID-19 infection was observed in individuals aged ≥80 who received three doses of BNT162b2 [75.5% (73.1-77.7%)] or three doses of CoronaVac [53.9% (51.0-56.5%)] compared to those in the younger age group who received three doses of BNT162b2 [51.1% (49.9-52.4%)] or three doses of CoronaVac [2.0% (-0.1-4.1%)]. VE (95% CI) was higher for other outcomes, reaching 91.9% (89.4-93.8%) and 86.7% (84.3-88.8%) against COVID-19-related hospitalization; 85.8% (61.2-94.8%) and 89.8% (72.4-96.3%) against COVID-19-related severe complications; and 96.4% (92.9-98.2%) and 95.0% (92.1-96.8%) against COVID-19-related mortality after three doses of BNT162b2 and CoronaVac in older vaccine recipients, respectively. A similar dose-response relationship was established in younger vaccine recipients and after stratification by sex and Charlson Comorbidity Index., Conclusion: Both BNT162b2 and CoronaVac vaccination were effective in protecting older adults against COVID-19 infection and COVID-19-related severe outcomes amidst the Omicron BA.2 pandemic, and VE increased further with the third dose., (© International Society of Travel Medicine 2022. Published by Oxford University Press.)

Objective: Anti-melanoma differentiation-associated protein 5 (MDA5)-positive DM is associated with rapidly progressive interstitial lung disease (RP-ILD) and high mortality. This multicentre retrospective study aimed to identify predictors of mortality and RP-ILD., Methods: Anti-MDA5-positive DM patients were identified from the Hong Kong Myositis Registry and the Clinical Data Analysis and Reporting System. Clinical characteristics were reviewed. Risk factors for mortality and RP-ILD were identified., Results: Among the 116 recruited patients, 100 (86.2%) had ILD, 47 (40.5%) had RP-ILD and 44 (37.9%) patients died. Cox regression analysis revealed RP-ILD [hazard ratio (HR) 9.735 (95% CI 3.905, 24.272)], age &gt;52 years [HR 4.750 (95% CI 1.692, 13.333)], ferritin level &gt;2800 pmol/l [HR 3.042 (95% CI 1.323, 6.997)] and lactate dehydrogenase (LDH) &gt;400 IU/l [HR 2.290 (95% CI 1.009, 5.198)] were independent predictors of mortality. With regard to RP-ILD, analyses showed that potential predictors at baseline included age &gt;50 years [HR 2.640 (95% CI 1.277, 5.455)], LDH &gt;300 IU/l [HR 3.189 (95% CI 1.469, 6.918)], fever [HR 1.903 (95% CI 0.956, 3.790)] and neutrophil:lymphocyte ratio &gt;7.0 [HR 1.967 (95% CI 0.942, 4.107)]. We proposed a prediction model based on fever, LDH, age and white cell count (FLAW) to stratify the risk of development of RP-ILD. The probability of RP-ILD in a patient with a score of 4 was 100%. A small internal validation cohort showed the odds of RP-ILD with FLAW scores of 0, 1, 2 and 3 were 0%, 0%, 42.9% and 75%, respectively., Conclusions: Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates. The FLAW model maybe useful to predict the development of RP-ILD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort., 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The ability to clone genes has greatly advanced cell and molecular biology research, enabling researchers to generate fluorescent protein fusions for localization and confirm genetic causation by mutant complementation. Most gene cloning is polymerase chain reaction (PCR)�or DNA synthesis-dependent, which can become costly and technically challenging as genes increase in size, particularly if they contain complex regions. This has been a long-standing challenge for the Chlamydomonas reinhardtii research community, as this alga has a high percentage of genes containing complex sequence structures. Here we overcame these challenges by developing a recombineering pipeline for the rapid parallel cloning of genes from a Chlamydomonas bacterial artificial chromosome collection. To generate fluorescent protein fusions for localization, we applied the pipeline at both batch and high-throughput scales to 203 genes related to the Chlamydomonas CO2 concentrating mechanism (CCM), with an overall cloning success rate of 77%. Cloning success was independent of gene size and complexity, with cloned genes as large as 23 kb. Localization of a subset of CCM targets confirmed previous mass spectrometry data, identified new pyrenoid components, and enabled complementation of mutants. We provide vectors and detailed protocols to facilitate easy adoption of this technology, which we envision will open up new possibilities in algal and plant research., (� American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The Roche Cobas c513 (c513) is a dedicated stand-alone high throughput HbA1c analyzer. We evaluated the performance and the difference in turnaround times (TAT) of the c513 against our Cobas 8000 c502 (c502)., Methods: We assessed the linearity and precision of the c513, and its agreement (Deming regression and Bland-Altman analysis) with the c502 assay. We compared TAT for these analyzers for a single run of 50 samples and for all samples run over 2 comparable time periods., Results: The c513 assay was linear from 4.4-18.3% HbA1c. Interassay precision (CV%) was 1.2 and 0.8 at HbA1c levels of 5.7 and 10.5%, respectively. The c513 assay showed excellent concordance with the c502 assay (r = 0.997) with no significant difference between methods by Bland-Altman analysis (mean difference = 0.021% HbA1c, P = 0.1422). The c513 took 17 min to analyze 50 samples, compared to 40 min on the c502. Over comparable 2-month periods, 90% of samples requiring HbA1c tests only were completed under 25 min (c513) vs 30-35 min (c502). For tubes sharing complete blood count (CBC) testing with HbA1c, the 90th percentile TAT was 35-40 min (c513) compared to 45-50 min (c502)., Conclusion: The c513 assay performs well with excellent correlation to the c502 assay. The improved TAT of the c513 is suitable when there are demands for rapid HbA1c results and it may forestall requests for point-of-care testing. It is also attractive to sites with heavy workloads with a claimed throughput of 400 tests / h., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please contact: journals.permissions@oup.com.)

Background: Little is known about the performance of the Roche novel severe acute respiratory syndrome coronavirus 2 antibody (anti-SARS-CoV-2) assay. We provide an extensive evaluation of this fully automated assay on Cobas e801/e602 immunoassay analyzers., Methods: We assessed the linearity, precision, and throughput of the Roche anti-SARS-CoV-2 assay. Sensitivity was calculated from 349 SARS-CoV-2 polymerase chain reaction (PCR) positive samples; specificity was determined from 715 coronavirus disease 2019 (COVID-19)-naive samples. We examined cross-reactivity against other antibody positive samples [syphilis, rheumatoid factor (RF), antinuclear antibody (ANA), double-stranded DNA (ds-DNA), influenza, dengue, hepatitis B (HBV), hepatitis C (HCV)] and the anti-SARS-CoV-2 kinetics., Results: The assay cut-off index (COI) was linear up to 90.8. The interassay precision was 2.9% for a negative control (COI = 0.1) and 5.1% for a positive control (COI = 3.0). Assay time is 18 min and results are available 1 min later; throughput for 300 samples was 76 min. Only 1 case positive for HBsAg tested falsely positive; specificity was 99.9%. The assay has a sensitivity of 97.1% 14 days after PCR positivity (POS) and 100% at ≥21 days POS; 48.2% of cases had anti-SARS-CoV-2 within 6 days POS. In 11 patients in whom serum was available prior to a positive antibody signal (COI ≥1.0) the interval between the last negative and first positive COI (time to "seroconversion") on average is 3 days (range 1-6 days) and 4 more days (range 1-7) for the anti-SARS-CoV-2 to plateau., Conclusion: The Roche anti-SARS-CoV-2 assay shows excellent performance with minimal cross-reactivity from other viral and confounding antibodies. Antibody development and seroconversion appears quite early., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the association of spinal inflammation on MRI in patients with various clinical, functional and radiological outcomes in patients with axial spondyloarthritis (SpA)., Methods: Three hundred and ninety-seven participants with axial SpA and back pain were recruited from 10 rheumatology centres. Clinical, biochemical and radiological parameters were collected and participants underwent MRI of the spine. MRI features including inflammatory lesions of facet joints and costovertebral joints, corner inflammatory lesions, and spondylitis were assessed. BASFI, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Global Index, BASMI and modified Stoke Ankylosing Spondylitis Spinal Score were measured. Multivariate linear regression models were used to determine the associations between MRI parameters and various clinical, functional and radiological outcomes., Results: BASMI and BASFI correlated well with inflammatory features in spinal MRI. Multivariate analysis showed that lumbar facet joint inflammation was independently associated with BASMI (regression coefficient (β) = 0.12, P < 0.001), lumbar spinal flexion (β = 0.13, P = 0.00), lateral spinal flexion (β = 0.09, P = 0.04), tragus-to-wall distance (β = 0.16, P < 0.001) and BASFI (β = 0.14, P = 0.01). Costovertebral joint inflammation was also associated with BASMI (β = 0.08, P = 0.05)., Conclusion: Inflammatory lesions of facet and costovertebral joints in MRI are associated with restriction in spinal mobility and functional impairment. These important yet commonly overlooked lesions should be reviewed in clinical practice in patients with SpA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance., Methods: We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated., Results: C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level., Conclusion: MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: Two versions of a patient-based DAS (PDAS) 1 and 2 (with and without ESR) have been developed and validated in RA. The objective of this study was to define PDAS1- and PDAS2-based criteria for remission, low, moderate and high disease activity and responses to treatment., Method: Using receiver operating characteristic curves, the optimal thresholds for PDAS1 and PDAS2 that correspond to validated assessor-based DAS (DAS28) and Clinical Disease Activity Index (CDAI) disease statuses were determined. Data from RA patients initiated on disease-modifying drugs were used to determine optimal thresholds for PDAS1 and PDAS2 that corresponded to EULAR good and moderate responses. Agreement with DAS28, CDAI and EULAR response criteria was assessed by Cohen's κ statistic., Results: Threshold for PDAS1 and PDAS2 demonstrated fair to moderate agreement with DAS28 [κ = 0.44 (95% CI: 0.40, 0.50) and 0.31 (95% CI: 0.25, 0.38)] and CDAI [κ = 0.27 (95% CI: 0.22, 0.33) and 0.42 (95% CI: 0.35, 0.49)] disease statuses, respectively, which was similar to agreement between DAS28 and CDAI [κ = 0.54 (95% CI: 0.46, 0.61)] within this group. Agreement of EULAR good and moderate response with PDAS1 and PDAS2 was κ = 0.46 (95% CI: 0.27, 0.64) and 0.38 (95% CI: 0.20, 0.56), respectively., Conclusion: Thresholds for disease activity statuses and response to treatment for PDAS1 and PDAS2 have been established. They have comparable agreement to assessor-based criteria., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate left ventricular (LV) function and carotid intima-media thickness (IMT) in patients with axial SpA in relationship to underlying disease severity., Methods: We recruited 104 patients with axial SpA and 50 controls. Detailed transthoracic echocardiography was performed and analysed with two-dimensional speckle tracking strain analysis for systolic function and tissue Doppler-derived E/E' for diastolic function assessment. Carotid IMT was measured by ultrasonography to evaluate subclinical atherosclerosis. Radiological severity of patients with axial SpA was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)., Results: Despite a similar LV ejection fraction [62.7% (s.d. 3.9) vs 62.8% (s.d. 3.8), P = 0.83], patients with axial SpA had impaired LV myocardial longitudinal strain (LS), circumferential strain (CS) and radial strain (RS) compared with controls [-18.1% (s.d. 2.4) vs -20.1% (s.d. 2.5), -17.2% (s.d. 2.2) vs -20.3% (s.d. 2.9) and 37.1% (s.d. 8.6) vs 43.2% (s.d. 10.9), respectively; all P < 0.01]. In addition, patients with axial SpA had a greater E/E' [7.9 (s.d. 2.5) vs 7.0 (s.d. 1.7), P < 0.01] and carotid IMT [0.78 mm (s.d. 0.19) vs 0.69 mm (s.d. 0.10), P < 0.01] than controls. After adjusting for potential confounding factors, axial SpA remained independently associated with LV myocardial strains, E/E' and carotid IMT. Importantly, multivariate linear regression analysis demonstrated that mSASSS was independently associated with LV longitudinal strain, E/E' and carotid IMT., Conclusion: Our study demonstrated that patients with axial SpA had impaired LV systolic and diastolic function and increased carotid IMT. Importantly, mSASSS was independently associated with LV longitudinal strain, E/E' and carotid IMT after adjusting for confounding factors. Speckle tracking echocardiography may be a useful tool for early detection of impaired LV function in patients with SpA and carotid IMT examination can provide valuable assessment of subclinical atherosclerosis in patients with SpA., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients., Methods: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering., Results: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations., Conclusion: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.

Xylose oligomers are the intermediate products of xylan depolymerization into xylose monomers. An understanding of xylan depolymerization kinetics is important to improve the conversion of xylan into monomeric xylose and to minimize the formation of inhibitory products, thereby reducing ethanol production costs. The study of xylan depolymerization requires copious amount of xylose oligomers, which are expensive if acquired commercially. Our approach consisted of producing in-house oligomer material. To this end, birchwood xylan was used as the starting material and hydrolyzed in hot water at 200 °C for 60 min with a 4 % solids loading. The mixture of xylose oligomers was subsequently fractionated by a centrifugal partition chromatography (CPC) with a solvent system of butanol:methanol:water in a 5:1:4 volumetric ratio. Operating in an ascending mode, the butanol-rich upper phase (the mobile phase) eluted xylose oligomers from the water-rich stationary phase at a 4.89 mL/min flow rate for a total fractionation time of 300 min. The elution of xylose oligomers occurred between 110 and 280 min. The yields and purities of xylobiose (DP 2), xylotriose (DP 3), xylotetraose (DP 4), and xylopentaose (DP 5) were 21, 10, 14, and 15 mg/g xylan and 95, 90, 89, and 68 %, respectively. The purities of xylose oligomers from this solvent system were higher than those reported previously using tetrahydrofuran:dimethyl sulfoxide:water in a 6:1:3 volumetric ratio. Moreover, the butanol-based solvent system improved overall procedures by facilitating the evaporation of the solvents from the CPC fractions, rendering the purification process more efficient.

Populus sp. are hardwood feedstocks that grow in forest management areas that are logged for softwoods; however, they are also being considered as an energy-destined feedstock. The objective of this work was to determine the effect of xylose yield from dilute acid and hot water pretreatments performed in unstirred batch stainless steel reactors at temperatures ranging from 140 to 200°C. Populus deltoides clones S13C20 and S7C15 used in this study originated from Eastern Texas and were cultivated for 14 years in Pine Tree, AR. P. deltoides clones S13C20 and S7C15 had specific gravities of 0.48 and 0.40, respectively. Bark and wood were examined separately. As expected, hot water pretreatments, in the tested temperature range, resulted in very little direct xylose recovery. However, the 140°C dilute acid pretreatment of the lower specific gravity clone, S7C15, wood yielded the highest average xylose recovery of 56%. This condition also yielded the highest concentration of furfural, 9 mg/g sample, which can be inhibitory to the fermentation step. The highest xylose recovery from bark samples, 31%, was obtained with clone S7C15, using the 160°C dilute acid pretreatment for 60 min.

Xylose oligomers, which have a prebiotic effect, have been used as additives to human and animal food. These oligomers are also the primary intermediate in hemicellulose degradation during the pretreatment of biomass. Centrifugal partition chromatography (CPC) was used in this study to separate and purify xylan-derived oligomers from birchwood xylan. The xylan was partially hydrolyzed to achieve varying degrees of polymerization at 130°C using 0.98% aqueous sulfuric acid for 20 min with a 2.5% solid loading. The CPC solvent system consisting of dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and water in a 1:6:3 volumetric ratio was used because of its ability to dissolve xylose oligomers of different degrees of polymerization. The CPC was operated in the ascending mode with the water- and DMSO-rich bottom phase acting as the stationary phase, while the THF-rich top phase was the eluent. This paper delineates a method for the production and purification of xylose monomer and xylose oligomers (up to xylopentaose) using CPC. The amount and purity of compounds collected from the CPC fractionation based on 1 g of birchwood xylan were 25.26 mg of xylose at 91.86% purity, 10.71 mg of xylobiose at 85.07% purity, 4.15 mg of xylotriose at 54.71% purity, 5.03 mg of xylotetraose at 38.33% purity and 3.31 mg of xylopentaose at 30.43% purity.

Objective: Since mycophenolate mofetil (MMF) has emerged as an immunosuppressant for treating proliferative lupus nephritis, the role of cyclophosphamide (CYC)-containing regimens is being challenged. Efficacy data from randomized controlled trials (RCTs) and previous meta-analyses comparing these two agents for treating lupus nephritis have been inconsistent as they were heterogeneous in design and of small sample size. An updated meta-analysis is therefore required., Methods: Publications in the English literature were searched with the keywords 'mycophenoate', 'mycophenolic', 'lupus nephritis', 'nephritis' and 'glomerulonephritis' for RCTs in electronic databases. Primary outcome was relative risk (RR) of renal remission at 6 months. Secondary outcome included RRs of mortality, development of end-stage renal failure (ESRF) and side effects. Meta-regression was performed to identify factors explaining the heterogeneity of the effect sizes., Results: Ten eligible RCTs involving 847 patients were included. MMF offers similar efficacy in inducing renal remission as CYC (RR 1.052; 95% CI 0.950, 1.166) and the risks of death (RR 0.709; 95% CI 0.373, 1.347) and ESRF (RR 0.453; 95% CI 0.183, 1.121) were comparable. Significantly fewer patients receiving MMF developed amenorrhoea (RR 0.212; 95% CI 0.094, 0.479) and leucopenia (RR 0.473; 95% CI 0.269, 0.832) while the risks of herpes infection and pneumonia tended to be lower and that of diarrhoea appeared higher in the MMF groups. Meta-regression revealed that the non-white and non-Asian ethnicities contributed significantly to the heterogeneity of the effect sizes of renal remission., Conclusion: MMF offers similar efficacy in renal remission and survival as CYC. MMF appears safer than CYC in the treatment of proliferative lupus nephritis.

Objectives: Patients with systemic lupus erythematosus (SLE) are susceptible to opportunistic infections. To examine the clinical manifestations of non-tuberculous mycobacterial (NTM) infections with those of Mycobacterium tuberculosis (MTB) infections in SLE patients., Methods: Medical records of a cohort of 725 SLE patients were reviewed for previous NTM infections. Demographic characteristics, predisposing factors and clinical outcomes were compared with patients who had previous MTB infections (n = 39)., Results: Eleven (nine female and two male) cases were identified (prevalence 1.5%). The mean +/- S.D. age at the time of infection was 42.8 +/- 13.9 yrs, 9.3 +/- 5.8 yrs after the onset of SLE. The mean +/- S.D. time taken from onset of symptoms to the diagnosis of NTM infection was 5.7 +/- 7.2 months. Sites of involvement included skin and soft tissue (n = 8), chest (n = 2) and disseminated infection (n = 1). NTM infections were more likely to involve extrapulmonary sites (P = 0.006), presented in patients with longer lupus disease duration (P < 0.001), occurred in older patients (P < 0.001) and in those who had a higher cumulative dose of prednisolone (P = 0.01) than MTB infections. Using a stepwise logistic regression, disease duration was found to be the only independent predictive factor (P = 0.005) for NTM infections. Ten (25.6%) patients with MTB infections but none of the patients with NTM infections presented concomitantly at the onset of SLE (P = 0.09). There were no differences in the recurrence rate (P = 0.64) and frequency of disseminated infections (P = 0.40) between NTM and MTB infections., Conclusions: NTM infections tended to develop in SLE patients later in their disease course than MTB infections. A high index of suspicion is required for its diagnosis.

Perfluorooctanoic acid (PFOA) is a persistent pollutant and is detectable in human serum (5 ng/ml in the general population of the Unites States). PFOA is used in the production of fluoropolymers which have applications in the manufacture of a variety of industrial and commercial products (e.g., textiles, house wares, electronics). PFOA is developmentally toxic and in mice affects growth, development, and viability of offspring. This study segregates the contributions of gestational and lactational exposures and considers the impact of restricting exposure to specific gestational periods. Pregnant CD-1 mice were dosed on gestation days (GD) 1-17 with 0, 3, or 5 mg PFOA/kg body weight, and pups were fostered at birth to give seven treatment groups: unexposed controls, pups exposed in utero (3U and 5U), lactationally (3L and 5L), or in utero + lactationally (3U + L and 5U + L). In the restricted exposure (RE) study, pregnant mice received 5 mg PFOA/kg from GD7-17, 10-17, 13-17, or 15-17 or 20 mg on GD15-17. In all PFOA-treated groups, dam weight gain, number of implantations, and live litter size were not adversely affected and relative liver weight increased. Treatment with 5 mg/kg on GD1-17 increased the incidence of whole litter loss and pups in surviving litters had reduced birth weights, but effects on pup survival from birth to weaning were only affected in 5U + L litters. In utero exposure (5U), in the absence of lactational exposure, was sufficient to produce postnatal body weight deficits and developmental delay in the pups. In the RE study, birth weight and survival were reduced by 20 mg/kg on GD15-17. Birth weight was also reduced by 5 mg/kg on GD7-17 and 10-17. Although all PFOA-exposed pups had deficits in postnatal weight gain, only those exposed on GD7-17 and 10-17 also showed developmental delay in eye opening and hair growth. In conclusion, the postnatal developmental effects of PFOA are due to gestational exposure. Exposure earlier in gestation produced stronger responses, but further study is needed to determine if this is a function of higher total dose or if there is a developmentally sensitive period.

Objective: Cyclin-dependent kinase inhibitor 1A (p21) is a negative regulator in the cell cycle. Development of sex-linked lupus-like syndrome in p21-/- mice and reduced p21 gene expression in patients with systemic lupus erythematosus (SLE) compared with those in healthy controls suggested that p21 is a susceptibility gene of SLE. We investigated the same by a case-control association study., Methods: Six single nucleotide polymorphisms, p21US G/A, p21DS C/A, p21-1022 G/A, p21C31 C/A, p21In2 G/C and p21UTR T/C, were genotyped in 516 SLE patients and 693 healthy controls. Association of genotypes and alleles with disease, disease phenotypes, haplotypes construction, linkage disequilibrium analysis and p21 mRNA expression were performed., Results: We found a significant association of p21US A allele (OR = 0.23, 95% CI: 0.14-0.38, P < 0.001) and p21-1022 A allele (OR = 1.95, 95% CI: 1.37-2.78, P < 0.001) with SLE. We identified significant differences in the frequencies of haplotypes ht1-ACACCC, which contains p21US A allele, and ht2-GCACCC, which contains p21-1022 A allele, between SLE patients and controls (P < 0.0001). Besides, the p21US GA was associated with SLE patients suffering from arthritis (P = 0.003). We also observed differential p21 mRNA expressions among different genotypes of p21US and p21-1022 which were statistically significant., Conclusion: Our results suggested that the p21US A allele and p21-1022 A allele were both associated with the development of SLE, and the p21US A allele was associated with arthritis in SLE patients.

Objectives: To investigate whether plasma adrenomedullin (AM) level is elevated in lupus nephritis and to examine if plasma AM level is correlated with systemic lupus erythematosus (SLE) disease activity and severity of lupus nephritis after multivariate adjustment., Methods: Consecutive SLE patients and healthy volunteers of age >/=16 were recruited from the rheumatology clinics of two hospitals in Hong Kong. SLE patients with nephritis fulfilled the American College of Rheumatology criteria for renal involvement and had percutaneous renal biopsy performed. Subjects were divided into three groups: (i) SLE patients with nephritis, (ii) SLE patients without nephritis and (iii) normal controls. The demographic and clinical variables were compared between these groups of patients and plasma AM level was determined by radioimmunoassay. Factors associated with plasma AM level were explored by regression analysis with adjustment of confounding factors., Results: Sixty SLE patients (39 with nephritis and 21 without) and 23 normal subjects were studied. The plasma AM level of SLE patients was significantly higher than that of normal controls. SLE patients with nephritis had significantly higher plasma AM level than those without nephritis and normal controls (P<0.001). In regression analysis, proteinuria was negatively associated with plasma AM level (P=0.006) whereas SLE disease activity index was positively associated with plasma AM level after multivariate adjustment (P=0.002)., Conclusions: Plasma AM is elevated in lupus nephritis, which correlates with lupus disease activity. It is negatively associated with urine protein excretion although it is unrelated to the type of renal pathology per se. Plasma AM may play a role to suppress the activity of lupus nephritis.

Objectives: To study the survival rate and prognostic indicators of systemic lupus erythematosus (SLE) in a southern Chinese population., Methods: One hundred and eighty-six patients with SLE diagnosed between 1992 and 1999 were prospectively followed. Clinical features at presentation, subsequent evolving features, autoantibody profile, damage scores and mortality data were obtained. Prognostic factors for survival were studied by statistical analysis., Results: One hundred and sixty-three female and 23 male SLE patients were studied. The female to male ratio was 7.1 to 1 and the mean age at presentation was 33.6 yr (range 12-75). The mean disease duration was 45.2 months. At diagnosis, arthritis, malar rash and alopecia were the commonest features. During follow-up, the prevalence of nephritis, arthritis, photosensitivity and haematological disease increased significantly. Thirty-one per cent of the patients had organ damage at the time of data analysis and renal disease was the commonest cause. Logistic regression revealed that central nervous system disease, discoid lesions and treatment with high-dose steroid were independent predictors for damage. Nine patients died during the study period (three of disease-related complications and six of infections). The 3-, 5-, and 7-yr survival rates of our cohort were 97, 93 and 93%, respectively. Cox regression analysis revealed that thrombocytopenia and high-dose steroid treatment were independent risk factors for mortality., Conclusions: The survival of SLE in our southern Chinese patients is similar to that of the Caucasian series reported in the 1990s. Although nephritis contributes to organ damage, it is not a major determinant for survival. Infection remains the commonest cause of death. High-dose steroid treatment and thrombocytopenia are independent risk factors for mortality. Judicious use of immunosuppressive agents is necessary to improve the short-term survival of SLE.

Objective: To evaluate the efficacy of calcitriol and hormonal replacement therapy (HRT) in the treatment of steroid-induced osteoporosis in hypogonadal women., Methods: We studied 28 young patients (aged 37 +/- 6 yr) with systemic lupus erythematosus (SLE) on chronic steroid therapy for 130 +/- 22 months and requiring more than 10 mg/day prednisone. They were amenorrhoeic for more than 2 yr with proven ovarian failure. All had osteopenia with a T score at L2-4 of less than -1. They were randomized to receive HRT (conjugated oestrogen 0.625 mg daily from day 1 to day 21 plus medroxyprogesterone acetate 5 mg daily days 10-21) or calcitriol 0.5 microg daily. All received calcium carbonate 1 g/day., Results: There were no differences in the baseline demographic, bone mineral density (BMD) and biochemical data between the two groups. Lumbar spine BMD increased by 2.0 +/- 0.4% after 2 yr with HRT (P<0.05), but reduced by 1.74 +/- 0.4% (P<0.05) with calcitriol treatment. No change was seen at the distal one-third radius with HRT treatment but significant bone loss (2.3 +/- 1.4%, P<0.02) was observed with calcitriol therapy. BMD at the hip did not change in both groups. Comparing both treatment groups, significant differences in the BMD at the spine (P<0.03) and radius (P<0.05) were seen at the end of 2 yr. The changes in urinary n-telopeptide excretion but not serum osteocalcin at 6 months and 12 months were inversely correlated with the changes in lumbar spine BMD at 24 months. HRT did not cause an adverse effect on SLE disease activity., Conclusion: HRT but not calcitriol could prevent bone loss in young hypogonadal women on chronic steroid therapy.

Objective: To study the predictive factors for avascular necrosis (AVN) of bone in patients with systemic lupus erythematosus (SLE)., Method: The records of 38 SLE patients who developed clinically apparent AVN during the course of their disease were reviewed. Information on clinical presentation, corticosteroid usage and autoantibody profiles was obtained, and comparison was made between these patients and 143 consecutive control SLE patients who did not have AVN., Results: The point prevalence of AVN in our SLE population was 12%. Patients with AVN, when compared with controls, had a significantly higher incidence of neurological disease (39% vs 14%; P < 0.001) and Cushingoid body habitus after steroid treatment (79% vs 53%; P = 0.004). The highest cumulative prednisolone dose in 1 and 4 months was significantly higher in the AVN group than the controls (1.8 vs 1.1 and 4.5 vs 2.8 g, respectively; P < 0.01 in both) and showed a linear trend with the incidence of AVN (chi2 test for trend, P < 0.01 in both). Lupus anticoagulant was associated with AVN (P = 0.02, odds ratio 2.88 [1.14-7.28]). Logistic regression analysis revealed that the highest cumulative prednisolone dose administered in 4 months, the maximum and mean daily prednisolone dosage, and the lupus anticoagulant were independent risk factors for AVN., Conclusions: Corticosteroid remains the major predisposing factor for AVN in SLE. Patients who require an initial high-dose steroid for disease control are at risk of AVN, especially if they are positive for the lupus anticoagulant or develop Cushingoid habitus after steroid treatment. High-risk patients should be closely monitored so that early AVN can be diagnosed by sensitive techniques such as magnetic resonance imaging and radioisotope bone scanning.

Prolactin (PRL) is an important immunoregulatory hormone secreted by the anterior pituitary gland. Hyperprolactinaemia has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, clinical studies regarding the PRL level and lupus disease activity have yielded contradictory results. The aim of our present study was, therefore, to re-evaluate the association of PRL level and disease activity in SLE by analysing a larger patient cohort and following them up serially. Seventy-two consecutive SLE patients were recruited and the serum PRL level was measured at each visit. Our results showed that hyperprolactinaemia (> 500 mIU/l) occurred in 35% (25/72) of the patients. A total of 72% (18/25) of the hyperprolactinaemic patients had mild elevation (arbitrarily defined as 500-800 mIU/l) of the level only. No correlation could be found between the PRL level and various clinical and serological parameters of lupus disease activity. On serial follow-up of 44 patients, again no correlation between PRL and disease activity could be demonstrated. We conclude that hyperprolactinaemia occurs in some patients with SLE, but the serum level of PRL does not correlate with clinical or serological disease activity and is not a reliable marker for disease monitoring. The mechanism and pathoaetiological and clinical significance of hyperprolactinaemia in a small subset of SLE patients remain unclear and a longer follow-up is necessary.

Nocardia is an important but often overlooked opportunistic infection agent in immunocompromised hosts. Nocardiosis is primarily pulmonary; central nervous system involvement, usually in the form of brain abscess, is less common. Primary nocardial meningitis without associated brain abscess and pulmonary lesion is extremely rare and poses a formidable diagnostic challenge. We report on a patient with systemic lupus erythematosus who presented with a clinical picture of chronic meningitis which failed to respond to empirical antibiotic treatment. She deteriorated and succumbed. Post-mortem examination showed nocardial meningitis without associated brain abscesses. Nocardial meningitis should be considered a differential diagnosis of subacute meningitis in immunocompromised hosts.

Maxepa contains eicosapentaenoic acid (EPA) (171 mg/capsule) and docosahexaenoic acid (DHA) (114 mg/capsule). EPA acts as an alternative substrate to arachidonate, leading to the formation of the less proinflammatory prostaglandins ('3' series) and leukotrienes ('5' series). If Maxepa has anti-inflammatory properties it could be expected to reduce the requirement for NSAIDs in patients with RA. This has not been investigated nor has Maxepa therapy been studied over a full 1-yr period. Sixty-four patients with stable RA requiring NSAID therapy only were studied. Patients received either 10 Maxepa or air-filled placebo capsules per day for 12 months. All then received placebo capsules for a further 3 months. Patients were reviewed at 3-monthly intervals. NSAID requirement at entry visit for each patient was assigned as 100%. Patients were instructed to slowly reduce their NSAID dosage providing there was no worsening of their symptoms. Clinical and laboratory parameters of RA activity were also measured. There was a significant reduction in NSAID usage in patients on Maxepa when compared with placebo from month 3 [mean (95% C.I. for mean) requirement--71.1 (55.9-86.2)% and 89.7 (73.7-105.7)%, respectively]. This effect reached its maximum at month 12 [40.6 (24.5-56.6)% and 84.1 (62.7-105.5)%, respectively] and persisted to month 15 [44.7 (27.6-61.8)% and 85.8 (60.5-111.1)%, respectively] (P < 0.001, ANOVA). These patients were able to reduce their NSAID requirement without experiencing any deterioration in the clinical and laboratory parameters of RA activity.

The role of polymorphonuclear cells (PMNs) in the pathophysiology of ischaemic vascular disease has been increasingly recognized in recent years. Activated PMNs may physically obstruct blood flow. Subsequent release of reactive oxygen radicals and lytic enzymes lead to continued damage. Previous studies have shown increased white cell activity in patients with secondary Raynaud's syndrome (RS). However, whether this is related to the underlying condition or to digital vasospasm is not clear. Using a more physiological whole blood PMN aggregation assay, we assessed PMN activity in 38 patients with severe Raynaud's phenomenon (RP) [16 had systemic sclerosis (SSc) and secondary RS; 22 had RP alone and no other features of a connective tissue disease]. Additionally, plasma levels of malondialdehyde (MDA), an indicator of free radical activity, were measured. Results were compared with those obtained from 56 matched volunteers. In order to assess if changes in PMN activity was directly related to digital vasospasm, patients were asked to record the duration and frequency of their Raynaud's attacks during a 2-week period using a pocket sized diary. Correlation between these clinical variables of Raynaud's severity and white cell activity was assessed. Patients with RP, both with and without SSc, showed a significantly greater fall in single PMN count when compared with control subjects [SSc associated RS 48.2 (41.4-56)% versus control, P = 0.04; RP alone 49.3 (46.8-52.1)% versus control, P = 0.01 (Mann-Whitney U-test)].(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously documented raised levels of factor VIII von Willebrand factor antigen (FVIII vWF Ag), an endothelial product, in patients with vascular diseases and suggested that levels of this relate to disease activity. No one has yet investigated patients with Raynaud's phenomenon (RP) alone to see if the severity of vasospastic attacks relates to FVIII vWF Ag. We studied 22 patients with RP. None of these patients fulfilled diagnostic criteria for a connective tissue disease but all had severe symptoms which warranted referral to hospital. We measured the FVIII vWF Ag and the procoagulant factor VIII (FVIII:c) levels in these patients. FVIII:c is not an endothelial product and is released by different mechanisms, thus it forms an active control to FVIII vWF Ag. FVIII vWF Ag measurements were carried out using the Laurell method and FVIII:c was assessed using the technique described by Nilsson. Patients were asked to complete diaries over a 2-week winter period. The frequency and duration of all Raynaud's attacks were recorded. There were significant positive correlations between FVIII vWF Ag and the total number and duration of RP attacks over the 2-week period (P less than 0.005, r = 0.67 and P less than 0.05, r = 0.40, respectively; Spearman's rank correlation). No correlation was found between levels of FVIII:c and the same clinical parameters. It has been suggested that patients with clinical evidence of vascular damage have elevated plasma levels of FVIII vWF Ag. Our present study has demonstrated correlations between FVIII vWF Ag levels and the clinical severity of vasospasm in patients with RP.(ABSTRACT TRUNCATED AT 250 WORDS)