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Objective To delineate the etiology, symptomatology, and treatment of sickle cell intrahepatic cholestasis (SCIC). Sickle cell disease (SCD) is the most frequently inherited hematologic disease, and SCIC is one rare and often fatal complication and comorbid disease. The literature contains only a small number of case reports involving SCIC and hence limited guidance can be obtained. Methods We reviewed the scientific literature to evaluate the science of SCIC to determine if there were consistencies in presentation, evaluation, treatment, and clinical outcomes. Results We reviewed 6 case reports and a limited number of clinical papers on SCIC. We reported consistencies in clinical presentation and treatment outcomes among cases as well as serological and hematological finding. Conclusions While there is some consistency in the symptom presentation of individuals with SCIC, reliable evaluation and clinical procedures were not demonstrated in what we reviewed. Further research is needed to delineate the attributes of this complicated disease that occurs within SCD.

Objectives To improve the definitions of inflammatory arthritis within the musculoskeletal (MSK) domain of the BILAG-2004 index by incorporating imaging findings and clinical features predictive of response to treatment. Methods The BILAG MSK Subcommittee proposed revisions to the BILAG-2004 index definitions of inflammatory arthritis, based on review of evidence in two recent studies. Data from these studies were pooled and analysed to determine the impact of the proposed changes on the severity grading of inflammatory arthritis Results The revised definition for severe inflammatory arthritis includes definition of “basic activities of daily living”. For moderate inflammatory arthritis, it now includes synovitis, defined by either observed joint swelling or MSK ultrasound evidence of inflammation in joints and surrounding structures. For mild inflammatory arthritis, the definition now includes reference to symmetrical distribution of affected joints and guidance on how ultrasound may help re-classify patients as moderate or no inflammatory arthritis. Data from two recent SLE trials were analysed (219 patients). 119 (54.3%) were graded as having mild inflammatory arthritis (BILAG-2004 C). Of these, 53 (44.5%) had evidence of joint inflammation (synovitis or tenosynovitis) on ultrasound. Applying the new definition increased the number of patients classified as moderate inflammatory arthritis from 72 (32.9%) to 125 (57.1%), while patients with normal ultrasound (n = 66/119) could be recategorised as BILAG-2004 D (inactive disease). Conclusions Proposed changes to the definitions of inflammatory arthritis in the BILAG 2004 index will result in more accurate classification of patients who are more or less likely to respond to treatment.

Keywords: Mars, Atmosphere, EMM, Emirates Mars Infrared Spectrometer, Off-axis Detectors.Introduction: The Emirates Mars Mission (EMM) Emirates Mars InfraRed Spectrometer (EMIRS) instrument is a Fourier Transform Infrared (FTIR) spectrometer designed to observe the Martian disk, with the primary scientific objective of determining the three-dimensional thermal state of the lower atmosphere and its diurnal variability on sub-seasonal timescales [1].EMIRS uses a 3x3 array of deuterated L-alanine doped triglycine sulfate (DLaTGS) pyroelectric detectors [1], however, following the integration of the EMIRS electronics with the optical and mechanical hardware it was observed that the performance of the off-axis (non-central) detectors of the array were lower than expected [1]. Investigations into the performance of these off-axis detectors has so far yielded inconclusive root causes. As EMIRS could meet its primary science objective with the on-axis (central) detector and was subject to a pressing instrument schedule, a project level decision was made to forgo any additional investigation and instead rely on the on-axis detector [1][2].Method: In this study we present a comparison of observations captured by EMIRS from the off-axis detectors against the on-axis detector. The comparison is performed via a top-down and bottom-up pathway approach using the EMM Science Team processing pipeline. The top-down pathway focuses on the effects of the pre-processing steps on the detector interferograms, whereas the bottom-up approach compares calibrated radiances derived from the pipeline with and without applying the pre-processing steps [3] [4]. Correction of these issues will expand the retrieval derived products by a factor of five.Results: The top-down comparison shows differences in terms interferogram amplitude and phase error between on and off-axis detectors. We assess the feasibility of correction, then apply correction methods to a subset of EMIRS observations, and propose the root cause of the issues. This study is presented along with the generation of a joint dataset of near-mutual EMIRS and EXI (Emirates eXploration Imager) observations [5].Acknowledgements: The authors would like to acknowledge support by a Joint Research Agreement between the Mohammed Bin Rashid Space Centre (MBRSC) and the National Space Science and Technology Center (NSSTC), UAE University (UAEU).References: [1] Edwards, C. S., et al. (2021). Space Science Reviews (2021) 217:77.[2] Amiri, H.E. S., et al. (2022). Space Science Reviews (2022) 218:4.[3] Forman, M. L., et al. (1966). J. Opt. Soc. Am. 56(1), 59–63.[4] Christensen, V.E., et al. (2018). Space Science Reviews (2018), 215:87.[5] Jones, A. R., et al. (2021). Space Science Reviews (2021) 217:81.

© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ., Background: Postgraduate rheumatology training programmes are already established at a national level in most European countries. However, previous work has highlighted a substantial level of heterogeneity in the organisation and, in part, content of programmes. Objective: To define competences and standards of knowledge, skills and professional behaviours required for the training of rheumatologists. Methods: A European Alliance of Associations for Rheumatology (EULAR) task force (TF) of 23 experts, including two members of the European Union of Medical Specialists (UEMS) section of rheumatology, was convened. The mapping phase consisted of the retrieval of key documents on specialty training in rheumatology and other related specialties across a broad set of international sources. The content of these documents was extracted and represented the foundation for the document draft that underwent several rounds of online discussion within the TF, and afterwards was also distributed to a broad group of stakeholders for collecting feedback. The list of generated competences was voted on during the TF meetings, while the level of agreement (LoA) with each statement was established by anonymous online voting. Results: A total of 132 international training curricula were retrieved and extracted. In addition to the TF members, 253 stakeholders commented and voted on the competences through an online anonymous survey. The TF developed (1) an overarching framework indicating the areas that should be addressed during training, (2) 7 domains defining broad areas that rheumatology trainees should master by the end of the training programme, (3) 8 core themes defining the nuances of each domain and (4) 28 competences that trainees should acquire to cover each of the areas outlined in the overarching framework. A high LoA was achieved for all competences. Conclusion: These points to consider for EULAR-UEMS standards for the training of European rheumatologists are now defined. Their dissemination and use can hopefully contribute to harmonising training across European countries., The project was funded by the European Alliance of Associations for Rheumatology (grant number EDU049).

Mars dust storms are an interdisciplinary field of research. They impact the entry-descent-landing operations of spacecraft, the energy production by the solar panels of Mars rovers and landers, and others. As can be foreseen, dust storms are also critical for the future human exploration of Mars. Dust storm research is directly aligned with the Emirates Mars Mission (EMM) science objective on the lower atmosphere, and with the science objective of correlating the lower and upper atmosphere [1,2]. First results of EMM dust storm research were reported in [3].EMM has a high-altitude orbit and provides data products for studies of the Mars atmosphere and surface with a near-hemispheric view. Moreover, EMM can provide information on dust storm activity every few hours or less. EMM observed multiple dust storms during the primary mission, including a large regional dust storm in Sep. and Oct. 2022.The focus of this presentation are unique dust storm observations by the EMM camera EXI [4]. We study a subset of dust storms, which is of particular interest to our research. The formation and growth of dust storms is followed at a (sub-)hourly time scale. This includes results on the dust storm morphology, wind direction, wind speed, surface dust lifting, etc.. Based on that, the implications for the physics and dynamics of dust storms are considered.[1] Amiri, H.E.S., Brain, D., Sharaf, O. et al. The Emirates Mars Mission. Space Sci Rev 218, 4 (2022). https://doi.org/10.1007/s11214-021-00868-x[2] Almatroushi, H., AlMazmi, H., AlMheiri, N. et al. Emirates Mars Mission Characterization of Mars Atmosphere Dynamics and Processes. Space Sci Rev 217, 89 (2021). https://doi.org/10.1007/s11214-021-00851-6[3] Gebhardt, C., Guha, B. K., Young, R. M. B., & Wolff, M. J. (2022). A frontal dust storm in the northern hemisphere at solar longitude 97—An unusual observation by the Emirates Mars mission. Geophysical Research Letters, 49, e2022GL099528. https://doi.org/10.1029/2022GL099528[4] Jones, A.R., Wolff, M., Alshamsi, M. et al. The Emirates Exploration Imager (EXI) Instrument on the Emirates Mars Mission (EMM) Hope Mission. Space Sci Rev 217, 81 (2021). https://doi.org/10.1007/s11214-021-00852-5

Objectives HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding. Methods Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models. Results We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049]. Conclusions There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study.

OBJECTIVE: To compare the responsiveness of the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity indices and to determine whether there was any added value in combining BILAG-2004, BILAG-2004 system tally (BST), or simplified BST (sBST) with SLEDAI-2K. METHODS: This was a multicenter longitudinal study of SLE patients. Data were collected on BILAG-2004, SLEDAI-2K, and therapy on consecutive assessments in routine practice. The external responsiveness of the indices was assessed by determining the relationship between change in disease activity and change in therapy between 2 consecutive visits. Comparison of indices and their derivatives was performed by assessing the main effects of the indices using logistic regression. Receiver operating characteristic curves analysis was used to describe the performance of these indices individually and in various combinations, and comparisons of area under the curve were performed. RESULTS: There were 1,414 observations from 347 patients. Both BILAG-2004 and SLEDAI-2K maintained an independent relationship with change in therapy when compared. There was some improvement in responsiveness when continuous SLEDAI-2K variables (change in score and score of previous visit) were combined with BILAG-2004 system scores. Dichotomization of BILAG-2004 or SLEDAI-2K resulted in poorer performance. BST and sBST had similar responsiveness as the combination of SLEDAI-2K variables and BILAG-2004 system scores. There was little benefit in combining SLEDAI-2K with BST or sBST. CONCLUSION: The BILAG-2004 index had comparable responsiveness to SLEDAI-2K. There was some benefit in combining both indices. Dichotomization of BILAG-2004 and SLEDAI-2K leads to suboptimal performance. BST and sBST performed well on their own; sBST is recommended for its simplicity and clinical meaningfulness.

Approximately two-thirds of patients discharged from an emergency department (ED) are prescribed at least one medication. Prescription clarification by outpatient pharmacies for ED patients can lead to delays for patients and added workload.This study aims to describe prescriptions requiring clarification prior to being dispensed by an outpatient pharmacy for patients recently discharged from an ED.This study was conducted at an urban, 61-bed academic ED. Prescription clarification forms were used to identify common causes for outpatient pharmacies to contact the ED to clarify prescriptions prior to dispensation. Clarification types were reviewed and classified. Descriptive statistics were used to present the classification types.There were 1278 documented calls to the ED for prescription clarification that were classified as clarification of directions for use (611, 47.7%), insurance or affordability issues (182, 14.2%), dose (172, 13.4%), medication availability (126, 9.8%), lost or missing prescription (93, 7.3%), patient allergy or adverse event (62, 4.8%), duplication in therapy (17, 1.3%), and clarification of medication ordered (17, 1.3%). When grouped into provider, system, or patient-related issues, provider issues were noted to be most frequent clarifications (862 clarifications, 67.3%), followed by system issues (325 clarifications, 25.4%), and finally, patient-related issues (93 clarifications, 7.3%).Clarification of directions for use, insurance or affordability issues, and clarification of the dose were the most common reasons that outpatient pharmacies contacted an ED regarding a prescription for a recently discharged patient.

The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.

Background/Aims Baricitinib, an oral selective JAK 1/2 inhibitor, is approved for treating adults with moderate-to-severe active rheumatoid arthritis (RA). This analysis aims to report the efficacy of baricitinib in patients with moderate RA at weeks (W)12 and 24 from two phase III studies, RA-BEAM (NCT01710358) and RA-BUILD (NCT01721057). Methods This post-hoc analysis included patients from RA-BEAM (inadequate responders to methotrexate) and RA-BUILD (inadequate responders to conventional synthetic DMARDs) with moderate RA at baseline (defined as Disease Activity Score (DAS)-28 with C-reactive protein (CRP) of > 3.2 and ≤5.1). This analysis reports treatment response as low disease activity (LDA) defined by DAS28-CRP ≤3.2 and >2.6 or remission defined by Results At baseline, moderate RA was observed in 117 patients on baricitinib 4-mg, 80 on adalimumab, and 133 on placebo in RA-BEAM; and 80 on baricitinib 2-mg, 63 on baricitinib 4-mg, and 73 on placebo in RA-BUILD. In RA-BEAM at W12, 46.2%, 37.5%, and 9.0% of patients on baricitinib 4-mg, adalimumab, and placebo, respectively, achieved remission. In RA-BUILD at W12, 38.8%, 44.4%, and 13.7% of patients on baricitinib 2-mg, baricitinib 4-mg, and placebo, respectively, achieved remission. At W24, a further increase in the percentage of patients achieving remission was reported in both trials (Table). Improvement in pain (VAS), FACIT-F, and HAQ-DI was similar across RA-BEAM and RA-BUILD with baricitinib treatment (Table). In both trials, patients reported improvement in duration and severity of morning stiffness, worst tiredness, and worst joint pain with baricitinib treatment (Table). Additionally, baricitinib treatment yielded numerical improvement in impairment of daily activity and work productivity in RA-BEAM (Table). Conclusion In patients with moderate RA, baricitinib markedly improved signs and symptoms of RA and patient-reported outcomes (PROs) at W12 and W24. Disclosure B.W. Kirkham: Member of speakers’ bureau; B.K. has received speaker’s payments from AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. Grants/research support; B. K. has received research support from Eli Lilly and Company and Novartis. Other; B. K. has been an adviser for AbbVie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, and UCB. B. W. has received meeting support payments from Eli Lilly and Company. E. Nikiphorou: Honoraria; E.N. received speaker honoraria from Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. Grants/research support; E.N. holds grants from Pfizer and Eli Lilly and Company. Other; E.N. participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Eli Lilly and Company, and Fresenius. E. N. received travel payments from Eli Lilly and Company. C.J. Edwards: Honoraria; C.E received honoraria from Eli Lilly and Company. Grants/research support; C.E. received grant payments from Abbvie, Pfizer, Roche, Biogen, and Eli Lilly and Company. Other; C.E. received personal fees from Abbvie, Astra-Zeneca, BMS, Celltrion, Fresenius, Galapagos, Gilead, GSK, Janssen, Roche, Pfizer, and Sanofi and travel and meeting payments from Eli Lilly and Company. M. Sheesh: Corporate appointments; M. S. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; M. S. is a minor shareholder at Eli Lilly and Company. E. Haladyj: Corporate appointments; E. H. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; E. H. is a minor shareholder at Eli Lilly and Company. J. Gerwien: Corporate appointments; J. G. is a full-time employee at Eli Lilly and Company. Shareholder/stock ownership; J. G. is a minor shareholder at Eli Lilly and Company. L. Zaremba-Pechmann: Corporate appointments; L. Z-P is a contractor at HaaPACS gmbH. P.C. Taylor: Consultancies; P. T. has been a consultant for AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly and Company, BMS, Pfizer, Roche, Celltrion, Sanofi, Nordic Pharma, Fresenius, and UCB. Grants/research support; P. T. received grant/research support from Galapagos. Other; P. T. has received meeting support payments from Eli Lilly and Company.

Background/Aims If sustained disease control is achieved in RA then tapering is supported by recommendations. However, this may cause loss of disease control with subsequent damage. A problem in assessing tapering is the short-term nature of studies. We wanted to explore the long-term use of tapering strategies. Methods Our biologics database has collected information since 2005. Our approach, refined with PPI, for people receiving TNF inhibitors (TNFi) has been to dose taper by one-third and then 50% if remission was achieved (DAS286 months apart, no corticosteroids). We initially required absence of power doppler (PD) in the hands (stopped in 2017). Failure of tapering was defined as a flare (DAS28>2.6, PD synovitis or patient-reported) resulting in a return to full dose, stopping the TNFi, or changing to another advanced therapy (bDMARD, tsDMARD). We explored associations between time on dose-reduction therapies and individual characteristics. Results 1180 patients started biological therapies during 2005-2021 with 668 receiving a TNFi. 119 (18%) were dose-tapered by one-third and of these 40 (30%) then by one-half. Over median follow-up of 2.2 years (IQR 0.7,5.9) with maximum follow-up of 8.93 years, tapering failed in 88 (74%). Of those failing, 50% achieved DAS28 remission, 18% low disease activity (LDA), 32% moderate (MDA) and none high (HDA) within 12 months. A Kaplan-Meier plot showed one-third of individuals failed tapering within the first year with two-thirds by 3 years. Logistic regression showed (Table 1) no significant effect of age, sex, time between diagnosis and TNFi, seropositivity, smoking, or DAS28 score. However, there was an association between concomitant use of methotrexate and reduced failure of tapering (HR 0.60 (CI 0.39,0.94) p = 0.03). Conclusion In a real-world setting, tapering is well accepted and occurred in around 20% of individuals. Two-thirds maintain tapering after 1 year with around one-third by 3 years. Predictors of success are limited although concurrent methotrexate use appears associated with continued tapering. However, around a third of patients who fail tapering do not return to remission/LDA when the full dose of TNFi is restarted. Disclosure M. Lwin: None. N. Nooh: None. C.R. Holroyd: Member of speakers’ bureau; Abbvie, BMS, Celltrion, Chugai, Galapagos/Gilead, Janssen, Lilly, Napp, Novartis, Pfizer, Roche and UCB. Other; Sponsorship / advisory board: Abbvie, BMS, Celltrion, Chugai, Galapagos/Gilead, Janssen, Lilly, Napp, Novartis, Pfizer, Roche and UCB. S.X. Lin1: None. D. Culliford: None. S.D. Fraser: None. C.J. Edwards: Member of speakers’ bureau; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Grants/research support; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Other; Advisory boards: Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung.

ObjectivesTo describe selected baseline characteristics, continuation with baricitinib and disease activity over time in patients initiating treatment with baricitinib in a UK real-world rheumatology setting.MethodsBaseline and follow-up data were analysed from baricitinib-treated patients newly recruited to the British Society for Rheumatology Biologics Registry–RA (BSRBR-RA) baricitinib cohort between 1 January 2018 and 31 March 2020. The primary objective was to evaluate continuation of baricitinib treatment in patients with at least one follow-up. Analyses were performed using the full baricitinib cohort, overall and by patient subgroup: biologic DMARD (bDMARD)/targeted synthetic (ts)DMARD-naive vs -experienced, baricitinib 4 vs 2 mg, age ≥65 vs ResultsAt baseline, the study cohort (n = 561) was 76.5% female, mean age 60.0 years, had longstanding (mean 13.1 years) and severe RA, and 54.0% had previously received a bDMARD/tsDMARD. Of 265 and 110 patients completing the 6- and 12-month follow-ups with available data, 77.7 and 69.1% remained on baricitinib at each time, respectively. In all Kaplan–Meier analyses, >60% of patients remained on baricitinib at 540 days. Continuation of baricitinib therapy differed between some subgroup pairs (bDMARD/tsDMARD naive/experienced, baricitinib 2 mg/4 mg). Disease activity was lower at both follow-ups than at baseline, overall and in all subgroups.ConclusionIn the early years of real-world baricitinib use in the UK, a high proportion of patients continued with treatment at both 6 and 12 months, at which times disease activity was lower than at baseline.

Objective To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined. Methods This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving fourth ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1 January 2005 to 31 December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage. Results A total of 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilizing at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI: 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states [BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA] were inversely associated with development of damage. Conclusions BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets.

To estimate the incidence of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies utilising different testing criteria, and review the clinical details of a series of patients with associated autoimmune myopathy.The incidence of anti-HMGCR antibodies in 2019 from 3 groups, South West London, Berkshire/Surrey and Southampton, were compared in the adult population. Anti-HMGCR antibodies were measured by commercial chemiluminescent and immunodot assays. The case notes of patients with anti-HMGCR antibodies were reviewed for the case series.The estimated incidence of anti-HMGCR antibodies in the first 2 groups was 1.94 per million adults per year, and in the third group 10.3 per million adults per year. In the first 2 groups the test criteria restricted analysis to specific clinician request for anti-HMGCR. In the third group test criteria included cases with less specific clinical features or a cytoplasmic indirect immunofluorescence anti-nuclear antibody pattern. The latter strategy had a positive predictive value of 66.1% for anti-HMGCR associated myopathy. A case series of 27 patients with anti-HMGCR antibodies revealed 19 with myopathy, oesophageal involvement in 26% and median peak CK 8000 IU/L. Response to treatment, including intravenous immunoglobulin, was good with CK normalising after median 5.5 months. In 8 cases there was no evidence of autoimmune muscle disease, 7 not statin exposed.Varying criteria result in a 5-fold difference in estimated incidence of anti-HMGCR antibodies, revealing positive cases without evidence of myopathy. Patients with anti-HMGCR myopathy respond well to immune suppression, supporting wider testing for these antibodies amongst patients with myopathy.

Background Loss of resistance (LOR) for epidural catheter placement has been utilized for almost a century. LOR is a subjective endpoint associated with a high failure rate. Nerve stimulation (NS) has been described as an objective method for confirming placement of an epidural catheter. We hypothesized that the addition of NS to LOR would improve the success of epidural catheter placement. Methods One-hundred patients were randomized to thoracic epidural analgesia (TEA) utilizing LOR-alone or loss of resistance plus nerve stimulation (LOR + NS). The primary endpoint was rate of success, defined as loss of sensation following test dose. Secondary endpoints included performance time. An intention-to-treat analysis was planned, but a per-protocol analysis was performed to investigate the success rate when stimulation was achieved. Results In the intention-to-treat analysis there was no difference in success rates (90% vs 82% [LOR + NS vs LOR-alone]; P = 0.39). The procedural time increased in the LOR + NS group (33.9 ± 12.8 vs 24.0 ± 8.0 min; P P = 0.017) when only patients in whom stimulation was achieved were included. Conclusions Addition of NS technique did not statistically improve the success rate for epidural placement when analyzed in an intention-to-treat format and was associated with a longer procedural time. In a per-protocol analysis a statistically higher success rate for patients in whom stimulation was obtained highlights the potential benefit of adding NS to LOR. Trial registration ClinicalTrials.gov identifier NCT03087604 on 3/22/2017; Institutional Review Board Wake Forest School of Medicine IRB00039522, Food and Drug Administration Investigational Device Exemption: G160273.

Objectives Moderately active RA is associated with poor patient outcomes. Despite this, some health systems have restricted access to advanced therapies to those with severe RA. There is also limited evidence of the efficacy of advanced therapies in the moderately active RA population. This post-hoc analysis from four phase 3 trials explored the efficacy of upadacitinib (UPA) for moderately active RA. Methods Patients included in this analysis received UPA 15 mg once daily [monotherapy after switching from MTX or in combination with stable background conventional synthetic DMARDs (csDMARDs)] or placebo. Clinical, functional and radiographic outcomes were analysed separately for patients with moderate disease activity {28-joint count DAS using CRP [DAS28(CRP)] of >3.2 and ≤5.1} and severe disease activity [DAS28(CRP) >5.1]. Results Patients with moderate disease activity who received UPA 15 mg (combination or monotherapy) after an inadequate response to biologic DMARDs and/or csDMARDs were significantly more likely to achieve a 20% improvement in the ACR response criteria, low disease activity status [DAS28(CRP) ≤ 3.2] or clinical remission [DAS28(CRP) Conclusion This analysis provides support for the use of UPA for the treatment of patients with moderate RA. Trial registration ClinicalTrials.gov: SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.

High-resolution simulations by the Regional Ocean Modeling System (ROMS) were used to investigate the dispersal of the San Francisco Bay (SFB) plume over the northern-central California continental shelf during the period of 2011 to 2012. The modeled bulk dynamics of surface currents and state variables showed many similarities to corresponding observations. After entering the Pacific Ocean through the Golden Gate, the SFB plume is dispersed across the shelf via three pathways: (i) along the southern coast towards Monterey Bay, (ii) along the northern coast towards Point Arena, and (iii) an offshore pathway restricted within the shelf break. On the two-year mean timescale, the along-shore zone of impact of the northward-dispersed plume is about 1.5 times longer than that of the southern branch. Due to the opposite surface Ekman transports induced by the northerly or southerly winds, the southern plume branch occupies a broader cross-shore extent, roughly twice as wide as the northern branch which extends roughly two times deeper due to coastal downwelling. Besides these mean characteristics, the SFB plume dispersal also shows considerable temporal variability in response to various forcings, with wind and surface-current forcing most strongly related to the dispersing direction. Applying constituent-oriented age theory, we determine that it can be as long as 50 days since the SFB plume was last in contact with SFB before being flushed away from the Gulf of the Farallones. This study sheds light on the transport and fate of SFB plume and its impact zone with implications for California’s marine ecosystems.

The incidence of bone cement implantation syndrome (BCIS) following cemented hemiarthroplasty for the treatment of hip fracture in the United States (US) population is not previously described. We sought to describe the incidence and factors associated with BCIS as well as its impact on mortality.In this retrospective observational study, electronic health records were examined for all relevant cases and BCIS was identified and graded according to accepted criteria. Demographic data was collected and an adjusted Cox proportional model was performed to determine the impact of severe BCIS on mortality.Following exclusions for documentation error and misclassification, 69 patients were included in the final analysis. BCIS, regardless of grade, was present in 24 (35%) patients, while severe BCIS (grades 2 and 3) was found in 7 (10%) of patients. Cox proportional hazard estimation adjusted for American Society of Anesthesiologists (ASA) grade, male sex, and age did not show severe BCIS to be independently associated with mortality, hazard ratio (CI) 1.96 (0.22-17.22).The incidence of BCIS in a selected hip fracture population is comparable in the US to those found in European studies. This study did not establish the occurrence of BCIS with mortality. As cemented hemiarthroplasty is recommended for displaced hip fractures and its use escalates in the US, one can expect an increase in the absolute number of patients experiencing BCIS as well.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

This systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Studies on GC efficacy were identified from a separate search on the efficacy of disease-modifying antirheumatic drugs (DMARDs). A combined search was performed for the duration of use and safety of GCs in RA patients. Dose-defined and time-defined GC treatment of any dose and duration (excluding intra-articular GCs) prescribed in combination with other DMARDs were considered. Results are presented descriptively. Two included studies confirmed the efficacy of GC bridging as initial therapy, with equal efficacy after 2 years of initial doses of 30 mg/day compared with 60 mg/day prednisone. Based on a recently performed SLR, in clinical trials most patients starting initial GC bridging are able to stop GCs within 12 (22% patients continued on GCs) to 24 months (10% patients continued on GCs). The safety search included 12 RCTs and 21 observational studies. Well-known safety risks of GC use were confirmed, including an increased risk of osteoporotic fractures, serious infections, diabetes and mortality. Data on cardiovascular outcomes were Inconsistent. Overall, safety risks increased with increasing dose and/or duration, but evidence on which dose is safe was conflicting. In conclusion, this SLR has confirmed the efficacy of GCs in the treatment of RA. In clinical trials, most patients have shown to be able to stop GCs within 12–24 months. Well-known safety risks of GC use have been confirmed, but with heterogeneity between studies.

ObjectivesTo perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).MethodsSLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.ResultsFifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9–2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.ConclusionThe safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.

The light-toned sedimentary layers that outcrop widely throughout Mars’ Southern Highlands have long been an enigma in uncovering the climatic history of Mars. Although these units seem to contain unique records of fluctuating surface conditions, the role of water in their formation is debated. A distinctive property of many such deposits is their elevated thermal inertia relative to that of surrounding materials. This temperature-controlling trait is often interpreted to indicate induration resulting from aqueous processes. However, prevalent erosional landforms suggest that the deposits host much weaker materials than neighboring units. We address this apparent contradiction by disentangling the relationships between thermal inertia, mineralogy, and erosion susceptibility and by quantifying the cohesion of layered deposits in the Arabia Terra region. We demonstrate that variations in dust cover associated with relative erodibility and eolian abrasion can be inconspicuous controls on apparent thermal inertia. We ultimately find that these deposits are not as cohesive as would be expected from a high water-to-rock ratio setting either during or after deposition. If water-rich surface conditions existed in the region after the Noachian, these deposits suggest they may have only been intermittent and fleeting.

International audience; Background In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. Methods We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. Results The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83-1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). Conclusion The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.

Background: the antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.Methods: this randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.Findings: between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.Interpretation: we found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.Funding: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

There is lots of educational content including free educational material for all those interested in rheumatic and musculoskeletal diseases (RMDs) on the EULAR School of Rheumatology (ESOR) website. It’s easy to access and just three clicks can take you straight to the content you need. Search for ESOR in your web browser (1), click on ‘catalog’, click on ‘free learning material’. Choose what you need, one more click, and you’re there. In particular, the EULAR imaging library and EULAR learning material for RA will give you lots of images and slides to help with your presentations. EULAR has a long history of providing education for rheumatologists, health professionals in rheumatology and people with RMDs. This commitment to education is enshrined in the EULAR strategy and will always be a large part of what EULAR does.

ObjectivesTo update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA).MethodsThis systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022.ResultsOf 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission.ConclusionThe results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA.