Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.

Molecular epidemiology, clinical features and significance of Shiga toxin detection from routine testing of gastroenteritis specimens.

After introduction of faecal multiplex PCR that includes targets for stx1 and stx2 genes, we found stx genes were detected in 120 specimens from 111 patients over a 31-month period from 2018-2020 from a total of 14,179 separate tests performed. The proportion of stx1 only vs stx2 only vs stx1 and stx2 was 35%, 22% and 42%, respectively. There were 54 specimens which were culture positive, with 33 different serotypes identified, the predominant serotype being O157:H7 (19%). Eighty-two patients had clinical data available; we found a high rate of fever (35%), bloody diarrhoea (34%), acute kidney injury (27%), hospital admission (80%) and detection of faecal co-pathogens (23%). Only one patient developed haemolytic uraemic syndrome. We found no significant association with stx genotype and any particular symptom or complication. We found a significant association of serotypes O157:H7 and O26:H11 with bloody stool, but no significant association with any other symptom or complication.

Association of Modified Systemic Lupus Erythematosus Responder Index Attainment With Long-Term Clinical Outcomes: A Five-Year Prospective Study.

OBJECTIVE: In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up. METHODS: We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied. RESULTS: We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P < 0.05 for damage accrual ORs at all time points). CONCLUSION: In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

Long-Term Outcomes in Patients on Life-Long Antibiotics: A Five-Year Cohort Study.

BACKGROUND: Little is known about the impacts at an individual level of long-term antibiotic consumption. We explored health outcomes of long-term antibiotic therapy prescribed to a cohort of patients to suppress infections deemed incurable. METHODS: We conducted a 5-year longitudinal study of patients on long-term antibiotics at Monash Health, a metropolitan tertiary-level hospital network in Australia. Adults prescribed antibiotics for >12 months to suppress chronic infection or prevent recurrent infection were included. A retrospective review of medical records and a descriptive analysis was conducted. RESULTS: Twenty-seven patients were followed up during the study period, from 29 patients originally identified in Monash Health in 2014. Seven of the 27 patients (26%) died from causes unrelated to the suppressed infection, six (22%) ceased long-term antibiotic therapy and two (7%) required treatment modification. Fifteen (56%) were colonised with multiresistant microorganisms, including vancomycin resistant Enterococci, methicillin resistant Staphylococcus aureus, and carbapenem resistant Enterobacteriaciae. CONCLUSIONS: This work highlights the potential pitfalls of long-term antibiotic therapy, and the frailty of this cohort, who are often ineligible for definitive curative therapy.

Measurement of specific organ domains in lupus randomized controlled trials: a scoping review.

OBJECTIVE: Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs. METHODS: We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively. RESULTS: Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies. CONCLUSION: Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed.

Associations of improvement in laboratory tests with clinical outcomes in patients with active systemic lupus erythematosus: a multinational longitudinal cohort study.

BACKGROUND: The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE. METHODS: We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare. FINDINGS: We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79-208·31 for LLDAS, OR 0·22, 95% CI 0·10-0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20-18·98 for LLDAS, OR 0·42, 95% CI 0·20-1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09-3·53 for LLDAS, OR 0·33, 95% CI 0·15-0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10-2·67 for LLDAS, OR 0·53, 95% CI 0·30-0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54-15·07 for LLDAS, OR 0·49, 95% CI 0·20-1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive. INTERPRETATION: Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints. FUNDING: Abbvie.

Systemic lupus erythematosus: a clinical update.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease known for its complexity and heterogeneity. Striking diversity can be observed between individual patients, in terms of clinical manifestations, serological abnormalities, disease progression and response to therapy. Furthermore, dysfunction of a broad range of immune pathways underlies disease development and expression. An appreciation of this diversity is vital in order to diagnose accurately and appropriately treat patients with SLE as there is no one-size-fits-all diagnostic test or treatment. Optimal management involves identifying affected organs, assessing severity, differentiating activity from irreversible damage and tailoring immunosuppressive treatment accordingly. Non-pharmacological interventions, attention to disease and treatment-related comorbidities and addressing the significant impact on health-related quality of life are also crucial to maximising patient outcomes.

Clinician-reported outcome measures in lupus trials: a problem worth solving.

Systemic lupus erythematosus (SLE) remains a disease of high unmet clinical need. Because of substantial patient heterogeneity, the execution of clinical trials that successfully determine the efficacy of novel therapeutics compared with placebo is a continuous challenge. Clinician-reported outcome measures of treatment response used in SLE trials have evolved from the use of individual disease activity indices, including the SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), to composite responder definitions such as the SLE Responder Index (SRI) and BILAG-Based Composite Lupus Assessment (BICLA), which are based on these indices. However, these approaches have notable drawbacks and defining the optimal clinical trial outcome measure for SLE remains a research goal. In this Viewpoint, we explore the strengths and limitations of existing indices and composite assessments, illustrating features which should be investigated in future analysis of trial data. Further, we provide a platform from which to advance new approaches to endpoint design, which is crucial to improve the interpretability and success of subsequent clinical trials in SLE.

Perspectives of Patients With Rheumatic Diseases in the Early Phase of COVID-19.

OBJECTIVE: To determine health perceptions of patients with rheumatic diseases in the early phase of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Rheumatology patients at a single center received via text message the Australian Rheumatology Association COVID-19 information sheet and an invitation to participate in a deidentified survey. Patient concerns regarding risks conferred by their rheumatologic disease or medications, impact of receiving the information sheet on the likelihood of staying on medication, and acceptance of telehealth were ascertained. RESULTS: A total of 2,630 patients received the text message, and the survey response rate was 21% (n = 550). The mean ± SD age of the participants was 52 ± 15.2 years, and 75.3% were female. Participants' highest ranked concern was that their medications would increase the severity of their COVID-19 symptoms (76.1%). The highest levels of concern were seen in patients taking combination conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and/or a biologic/targeted synthetic DMARD. There was no association between prednisolone dose and concern. While 63% of patients planned to continue their antirheumatic medications, a further 30% were more likely to continue taking their medications because of receiving the information. Telehealth was acceptable to 98.4% of patients, but 28.1% felt this was only appropriate while infection control measures were in place. CONCLUSION: Concerns regarding the risk of COVID-19 among patients taking antirheumatic drugs are common. Proactive dissemination of information is needed to address misconceptions related to medication risk, improve medication adherence, and minimize the risk of flares. Telehealth is acceptable to most patients during the COVID-19 pandemic.

Utility of repeated antinuclear antibody tests: a retrospective database study.

BACKGROUND: Anti-nuclear antibody (ANA) testing is frequently used as a diagnostic or screening test in patients with inflammatory or musculoskeletal symptoms. The value of repeat testing is unclear. We sought to evaluate the frequency, utility, and cost of repeat ANA testing. The main objective was to assess the positive predictive value of a repeat ANA test for the diagnosis of rheumatological conditions associated with ANA. METHODS: In this retrospective cohort study, we analysed data from a single, multisite tertiary health network in Australia across a 7-year period. ANA and other autoimmune test results were obtained from the hospital pathology system with a positive ANA titre cutoff set at 1:160. Clinical information was sourced from clinical information systems on any patient who had a change in ANA result from negative to positive on repeat testing. The cost of repeated ANA testing was calculated using the Australian Government Medicare Benefits Schedule. FINDINGS: From March 19, 2011, to July 23, 2018, a total of 36 715 ANA tests were done in 28 840 patients at a total cost of US$675 029 (2018 equivalent). 14 058 (38·3%) of these ANA tests were positive. 7875 (21·4%) of the ordered tests were repeats in 4887 (16·9%) of the patients, among whom 2683 (54·9%) had initially negative tests, and 2204 (45·1%) had initially positive tests. 511 (19·0%) of the 2683 patients with initially negative tests had a positive result on at least one repeat test, with a median time to first positive result of 1·74 years (IQR 0·54-3·60). A change from negative to positive ANA was associated with a new diagnosis in only five (1·1%) of the 451 patients with clinical information available and no previous diagnosis of an ANA-associated rheumatological condition, yielding a positive predictive value of 1·1% (95% CI 0·4-2·7). INTERPRETATION: Repeat ANA testing after a negative result has low utility and results in high cost. FUNDING: Monash Health.

Wohlfahrtiimonas chitiniclastica Bloodstream Infection Due to a Maggot-infested Wound in a 54-Year-Old Male.

We report a case of Wohlfahrtiimonas chitiniclastica bacteremia and sepsis, in the setting of lower limb wounds with maggot infestation. This is the first documented infection by this organism in the Australasia/Pacific region, identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S ribosomal ribonucleic acid sequencing. Clinicians should be aware of this emerging pathogen.

Novel Methods of Incorporating Time in Longitudinal Multivariate Analysis Reveals Hidden Associations With Disease Activity in Systemic Lupus Erythematosus.

Objective: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. SLE is characterized by high inter-patient variability, including fluctuations over time, a factor which most biomarker studies omit from consideration. We investigated relationships between disease activity and biomarker expression in SLE, using novel methods to control for time-dependent variability, in a proof-of-concept study to evaluate whether doing so revealed additional information. Methods: We measured 4 serum biomarkers (MIF, CCL2, CCL19, and CXCL10) and 13 routine clinical laboratory parameters, alongside disease activity measured by the SLE disease activity index-2k (SLEDAI-2k), collected longitudinally. We analyzed these data with unsupervised learning methods via ensemble clustering, incorporating temporal relationships using dynamic time warping for distance metric calculation. Results: Data from 843 visits in 110 patients (median age 47, 83% female) demonstrated highly heterogeneous time-dependent relationships between disease activity and biomarkers. Unbiased magnitude-based hierarchical clustering of biomarker expression levels isolated a patient subset (n = 9) with distinctively heterogeneous expression of the 17 biological parameters, and who had MIF, CCL2, CCL19, and CXCL10 levels that were higher and more strongly associated with disease activity, based on leave-one-out cross-validated regression analysis. In the remaining subgroup, a time-dependent regression model revealed significantly stronger predictive power of biomarkers for disease activity, compared to a time-agnostic regression model. Despite no significant difference in simple magnitude, using dynamic time warping analysis to align longitudinal profiles revealed a large subset (n = 69) with significantly stronger associations between biological parameters and disease activity. This subgroup had significantly lower flare rates, disease activity and damage scores, suggesting this clustering is clinically meaningful. Conclusions: These results suggest associations between biological parameters and disease activity in SLE exist in a multi-dimensional time-dependent pattern, with implications for the analysis of biomarkers in SLE often used to identify therapeutic targets. Novel methods to analyse high-dimensional data and control for time-dependent variability may have broad utility in the study complex relationships between clinical and biological parameters.

Patients' perceived health information needs in inflammatory arthritis: A systematic review.

OBJECTIVES: To identify the breadth of the literature regarding patients' perceived health information needs related to inflammatory arthritis care. METHODS: A systematic scoping review of MEDLINE, EMBASE, CINAHL and PsycINFO was performed to identify relevant articles (1990 -2016) examining patients' perceived needs relating to health information in inflammatory arthritis. Data and themes were identified and categorised and risk of bias assessed. RESULTS: Twenty nine studies (11 quantitative, 14 qualitative and 4 mixed methods) from 4121 identified articles were relevant for inclusion. Most focussed on rheumatoid arthritis. Key findings included: (1) Reasons for seeking health information often focussed on gaining ownership over their condition and facilitating self-management. (2) Demographic differences in information needs were inconsistent, but women and younger patients generally reported more needs. (3) Desired information content was broad, and included targeted and practical information covering disease treatment and psychosocial wellbeing. (4) Preferred information delivery method was consultation with a Rheumatologist; however group sessions had advantages for psychosocial issues while written information provided useful supplementation. (5) Barriers to meeting health information needs were around timely access. CONCLUSIONS: Patients with inflammatory arthritis have high information needs, desiring practical and individualised information. When developing strategies to meet patients' information needs, aligning patient expectations with delivery methods that are accessible, cost-effective and flexible may help to optimize patient outcomes.

Patient-perceived health service needs in inflammatory arthritis: A systematic scoping review.

BACKGROUND: Care that is patient-centred is more likely to be sustainable and associated with improved health outcomes. This approach to care requires an understanding of patients' health service needs, yet few studies have directly investigated the perceived health service needs of people with inflammatory arthritis. OBJECTIVES: To systematically identify the existing literature relating to patient perceived health service needs for inflammatory arthritis. METHODS: A systematic review of MEDLINE, EMBASE, CINAHL, and PsycINFO was conducted (1990-2016). Studies examining patients' perceived needs relating to health services for inflammatory arthritis were identified. Descriptive data regarding study design and methodology were extracted and risk of bias assessed. Findings were collated and categorized thematically. RESULTS: In total, 27 of 1405 (16 qualitative, 9 quantitative, and 2 mixed-methods) studies were relevant. The main areas of perceived need related to (1) Communication: consumers wanted clear, empathic communication, and to be involved with decision-making. (2) Characteristics of ongoing care: adequate consultation length with continuity and timely care were valued. (3) Factors influencing care-seeking included individual attitudes, disease severity, finances and family expectations. (4) Allied health and complementary and alternative medicines (CAM) were perceived as useful by many. The reporting of CAM use to doctors was variable, with several factors contributing to under-reporting. CONCLUSIONS: This review identified patients' perceived needs for better communication with their health providers, the heterogeneity of influences determining when care is sought and preferences regarding non-pharmacologic therapies. Aligning patients' perceived needs with evidence-based therapy for people with inflammatory arthritis will be important in optimizing patient outcomes.

Bilateral hippocampal stroke secondary to acute cocaine intoxication.

Hippocampal infarction is a rare complication of cocaine use, with only two cases previously reporting this association. We present a 44-year-old male who developed a persistent amnesic syndrome following cocaine intoxication. Examination identified no other neurological deficits. Subsequent MRI brain revealed high FLAIR signals and diffusion restriction in the hippocampus and centrum semiovale bilaterally, consistent with infarction. These findings were in keeping with the results of formal neuropsychological testing where deficits in both verbal and visual episodic memory and learning capacity were identified, consistent with hippocampal dysfunction. In contrast to previous reports, this presentation occurred in the absence of other vascular risk factors or hypoxic insults.

Physiological reactivity during autobiographical narratives in older adults: the roles of depression and anxiety.

OBJECTIVES: Physiological reactivity (PR) describes the change in physiological functioning (e.g., heart rate, blood pressure, pulse pressure) that occurs after the induction of a stressful task. This study aims to understand the influence of mental health symptoms on patterns of PR during autobiographical narratives in an older adult sample. METHOD: Eighty older adults completed self-report measures regarding their symptoms of depression and anxiety. Next, their blood pressure was recorded while they completed two verbal autobiographical narratives. RESULTS: During the positive narrative, anxiety was positively associated with increased PR while depression was negatively associated with PR. During the negative narrative, a significant interaction occurred whereby anxiety was significantly positively associated with PR for those participants low in depression. DISCUSSION: The above results are explained in the context of the Tripartite Model of Depression and Anxiety, which predicts different patterns of PR as a function of mental health symptoms. Limitations and future directions are also discussed.