The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug.

Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = -1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = -0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.

Differences in management approaches for lupus nephritis within the UK.

Objectives: Outcomes of therapy for LN are often suboptimal. Guidelines offer varied options for treatment of LN and treatment strategies may differ between clinicians and regions. We aimed to assess variations in the usual practice of UK physicians who treat LN. Methods: We conducted an online survey of simulated LN cases for UK rheumatologists and nephrologists to identify treatment preferences for class IV and class V LN. Results: Of 77 respondents, 48 (62.3%) were rheumatologists and 29 (37.7%) were nephrologists. A total of 37 (48.0%) reported having a joint clinic between nephrologists and rheumatologists, 54 (70.0%) reported having a multidisciplinary team meeting for LN and 26 (33.7%) reported having a specialized lupus nurse. Of the respondents, 58 (75%) reported arranging a renal biopsy before starting the treatment. A total of 20 (69%) of the nephrologists, but only 13 (27%) rheumatologists, reported having a formal departmental protocol for treating patients with LN (P < 0.001). The first-choice treatment of class IV LN in pre-menopausal patients was MMF [41 (53.2%)], followed by CYC [15 (19.6%)], rituximab [RTX; 12 (12.5%)] or a combination of immunosuppressive drugs [9 (11.7%)] with differences between nephrologists' and rheumatologists' choices (P = 0.026). For class V LN, MMF was the preferred initial treatment, irrespective of whether proteinuria was in the nephrotic range or not. RTX was the preferred second-line therapy for non-responders. Conclusion: There was variation in the use of protocols, specialist clinic service provision, biopsies and primary and secondary treatment choices for LN reported by nephrologists and rheumatologists in the UK.

International Survey to Evaluate Current Options for Subcutaneous Injection of Methotrexate (MTX) and a New Button-Free MTX Autoinjector.

Purpose: Prefilled syringes (PFS) and various types of pens are available for subcutaneous injection of methotrexate (MTX) in patients with rheumatoid arthritis or moderate to severe psoriasis. A new MTX pen with modernized button-free autoinjection technology was developed as a successor to a button-activated pen (metoject®/metex® PEN). To assess the needs of users and the relevance of features of the new MTX autoinjector an international online survey was performed. Methods: A structured questionnaire was distributed to physicians, nurses and patients in Germany, France, and the United Kingdom. Participants received illustrations and information about features of the new MTX autoinjector. Results: In total, 189 rheumatologists, 111 dermatologists, 90 nurses, and 180 patients answered the questions. Specific reasons for a preference for the use of MTX pens over PFS could predominantly be assigned to the categories "dosing/administration" and "ease of use". The first impression of the new MTX autoinjector was positive in 82% of physicians, 87% of nurses, and 76% of patients, respectively. The four most important features of the new MTX autoinjector were 2-step autoinjector mechanism (receiving a mean 14.1 to 18.1 chips of a total of 100 chips), small injection volume (9.7 to 11.7 chips), 10 different doses for dose flexibility (8.0 to 13.2 chips), and short injection time below 5 seconds (8.5 to 11.1 chips). Conclusion: Arguments for the use of MTX pens as opposed to PFS predominantly refer to dosing/administration and ease of use. The new button-free MTX autoinjector combines a number of advantageous features identified by the international survey.

Subcutaneous injection of methotrexate (MTX) is an option to treat patients with specific inflammatory diseases. A new MTX autoinjector with button-free activation of the injection and no need to build a skin fold was developed to address some of the reasons for non-adherence. The importance of specific needs of users as well as the relevance of features of the new MTX autoinjector are unknown. Therefore, a structured questionnaire was distributed to physicians, nurses and patients in Germany, France, and the United Kingdom. Illustrations and information about features of the new MTX autoinjector were distributed to the participants. The results of the study show that arguments for the use of MTX pens as opposed to prefilled syringes predominantly affect the categories dosing/administration and ease of use followed by safety/side effects. In addition, the study identified four main advantageous features of the new MTX autoinjector, ie simplicity due to the 2-step button-free autoinjector mechanism, the small injection volume, 10 different doses for dose flexibility, and the short injection time below 5 seconds.

Evaluation of a Generative Language Model Tool for Writing Examination Questions.

OBJECTIVE: To describe an evaluation of a generative language model tool to write examination questions for a new elective course focused on the interpretation of common clinical laboratory results being developed as an elective for students in a Bachelor of Science in Pharmaceutical Sciences program. METHODS: A total of 100 multiple-choice questions were generated using a publicly available large language model for a course dealing with common laboratory values. Two independent evaluators with extensive training and experience in writing multiple-choice questions evaluated each question for appropriate formatting, clarity, correctness, relevancy, and difficulty. For each question, a final dichotomous judgment was assigned by each reviewer, usable as written or not usable written. RESULTS: The major finding of this study was that a generative language model (ChatGPT 3.5) could generate multiple-choice questions for assessing common laboratory value information but only about half the questions (50% and 57% for the 2 evaluators) were deemed usable without modification. General agreement between evaluator comments was common (62% of comments) with more than 1 correct answer being the most common reason for commenting on the lack of usability (N = 27). CONCLUSION: The generally positive findings of this study suggest that the use of a generative language model tool for developing examination questions is deserving of further investigation.

Evaluating residual anti-Xa levels following discontinuation of treatment-dose enoxaparin in patients presenting for elective surgery: a prospective observational trial.

INTRODUCTION: Prior studies have demonstrated that patients presenting for elective surgery may have higher-than-expected residual anti-Xa level activity at or beyond 24 hours following their last treatment dose of enoxaparin. Given that 24 hours of abstinence is currently recommended by both European and American societies before the performance of neuraxial or deep anesthetic/analgesic procedures, determining the actual timeframe at which residual anti-Xa level activity reliably falls below 0.2 IU/mL, the lower limit of the target range for thromboprophylaxis, is critical. METHODS: This was a prospective observational trial. Consenting patients on treatment-dose enoxaparin were randomized to either a 24-hour group (last dose at 07:00 the day prior to surgery) or a 36-hour group (last dose at 19:00 2 days prior to surgery). On arrival for surgery, blood samples were obtained to assess residual anti-Xa level activity and renal function. The primary outcome was residual anti-Xa level activity following the last treatment dose of enoxaparin. Incorporating all patients, linear regression modeling was performed to predict the timepoint at which the level of anti-Xa activity reliably fell below 0.2 IU/mL. RESULTS: 103 patients were analyzed. Time from the last dose at which residual anti-Xa activity fell below 0.2 IU/mL, based on the upper bound of the 95% CI, was 31.5 hours. No correlation overall between age, renal function, or sex was found. CONCLUSION: Residual levels of anti-Xa activity do not reliably fall below 0.2 IU/mL 24 hours following discontinuation of treatment-dose enoxaparin. Therefore, current time-based guidelines are not conservative enough. Routine anti-Xa testing should be strongly considered, or current time-based guidelines should be reassessed. TRIAL REGISTRATION NUMBER: NCT03296033.

Revision to the musculoskeletal domain of the BILAG-2004 index to incorporate ultrasound findings.

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 US 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 US may help re-classify patients as moderate or no inflammatory arthritis. Data from two recent SLE trials were analysed (219 patients). A total of 119 (54.3%) were graded as having mild inflammatory arthritis (BILAG-2004 Grade C). Of these, 53 (44.5%) had evidence of joint inflammation (synovitis or tenosynovitis) on US. 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 US (n = 66/119) could be recategorized as BILAG-2004 Grade 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.

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Hypotension duration and vasopressor requirements following intrathecal oxytocin for Total hip arthroplasty: Secondary analysis of a randomized controlled trial.

INTRODUCTION: A recent publication investigating intrathecal oxytocin, 100 µg, administered immediately prior to a spinal anesthetic in patients undergoing primary total hip arthroplasty surgery demonstrated a reduction in disability for 3-weeks, increased walking distance at 8-weeks, and earlier opioid cessation. This secondary analysis study was undertaken to assess the acute cardiovascular safety and analgesic efficacy of intrathecal oxytocin in this study population. METHODS: 90 patients were included in the analysis (44 randomized to spinal oxytocin and 46 to placebo [saline]). Data collected prospectively during the previously published study were supplemented with additional retrospectively collected data. The primary outcomes were comparisons of the duration of hypotension (minutes with mean arterial pressure < 65 mmHg) and cumulative vasopressor requirements during the initial 60 min following spinal placement. Secondary outcomes included hypotension durations and vasopressor requirements at later time points, perioperative fluid administration, physical therapy metrics, time to first opioid administration, cumulative opioid consumption through 24 h, and verbal pain scores through 24 h. RESULTS: The duration of hypotension during the first 60 min following spinal placement did not differ between intrathecal oxytocin and placebo groups (12.2 ± 10.7 vs 14.0 ± 13.0 min, respectively; p = 0.476). There was also no difference in cumulative vasopressor requirements (1303 ± 883 vs 1156 ± 818 µg [phenylephrine equivalents]; p = 0.413) during that time period. No group differences were found for any of the investigated secondary outcomes. CONCLUSION: The administration of 100 µg of intrathecal oxytocin does not significantly impact the duration of hypotension or the need for vasopressor agents when given as a component of a spinal anesthetic. The oxytocin and placebo groups also did not differ in regards to physical therapy related metrics, time to first opioid administration, cumulative opioids at 24-h, or pain scores through 24-h. What is already known on this topic: Rapid intravenous oxytocin causes hypotension after cesarean delivery, but intrathecal oxytocin does not cause hypotension in healthy volunteers. WHAT THIS STUDY ADDS: Compared to saline control, intrathecal oxytocin, 100 µg did not increase the duration of hypotension or vasopressor requirements in patients during total hip arthroplasty. How this study might affect research, practice, or policy: Lack of hypotension from intrathecal oxytocin in this study supports future investigations to further explore its potential benefits, in terms of both analgesia and functional recovery following surgery.

Points to consider: EULAR-UEMS standards for the training of European rheumatologists.

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.

Characteristics of patients initiating treatment with baricitinib and outcomes at follow-up: analysis of BSRBR-RA Registry data.

OBJECTIVES: To 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. METHODS: Baseline 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 <65 years, monotherapy vs combination therapy and male vs female. RESULTS: At 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. CONCLUSION: In 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.

Evaluating the efficacy of upadacitinib in patients with moderate rheumatoid arthritis: a post-hoc analysis of the SELECT phase 3 trials.

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) < 2.6] by week 12/14 vs placebo. Statistically significant improvements in patient-reported functioning and pain from baseline were observed for UPA 15 mg vs placebo at week 12/14. Radiographic progression was also significantly reduced at week 26 compared with placebo. Similar improvements were observed for severe disease. 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.

Efficacy of subcutaneous vs intravenous infliximab in rheumatoid arthritis: a post-hoc analysis of a randomized phase III trial.

OBJECTIVES: The primary endpoint of the pivotal phase III study of infliximab (IFX) s.c. demonstrated non-inferiority of s.c. to i.v. IFX, based on 28-joint DAS-CRP (DAS28-CRP) improvement at week (W) 22 (NCT03147248). This post-hoc analysis investigated whether numerical differences in efficacy outcomes at W30/54 were statistically significant, using conservative imputation methods. METHODS: Patients with active RA and inadequate response to MTX received IFX i.v. 3 mg/kg at W0 and W2 (induction) and were randomized (1:1) to IFX s.c. 120 mg every 2 weeks or i.v. 3 mg/kg every 8 weeks thereafter (maintenance). Patients randomized to IFX i.v. switched to IFX s.c. from W30-54. This post-hoc analysis compared efficacy outcomes for s.c. and i.v. groups pre-switch (W30) and post-switch (W54) using last observation carried forward (LOCF) and non-responder imputation (NRI) methods. RESULTS: Of 343 randomized patients, 165 (IFX s.c.) and 174 (IFX i.v.) were analysed. At W30, significantly improved outcomes were identified with s.c. vs i.v. IFX for DAS28-CRP/DAS28-ESR/Clinical Disease Activity Index (CDAI)/Simplified Disease Activity Index (SDAI) scores (LOCF); ACR/good EULAR responses, DAS28-CRP/Boolean remission, and DAS28-CRP/DAS28-ESR/CDAI/SDAI low disease activity and remission (LOCF and/or NRI); and minimal clinically important difference in HAQ score (LOCF and NRI). After switching to IFX s.c. from IFX i.v., fewer significant between-group differences were identified at W54. CONCLUSION: IFX s.c. showed improved efficacy at W30 compared with IFX i.v., and the reduced between-group difference in efficacy outcomes at W54 after switching supports the results suggesting benefits of IFX s.c. compared with IFX i.v. at W30. TRIAL REGISTRATION: ClincialTrials.gov, http://clinicaltrials.gov, NCT03147248, https://clinicaltrials.gov/ct2/show/NCT03147248.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

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.

Comparison of Femoral Nerve Catheter, Adductor Canal Catheter, and Periarticular Liposomal Bupivacaine Infiltration for Postoperative Analgesia After Primary Total Knee Arthroplasty.

BACKGROUND: Peripheral nerve catheters are used to provide analgesia after total knee arthroplasty (TKA) and have been shown to decrease pain and opioid use, to facilitate participation with physical therapy (PT), and to hasten discharge. More recently, pericapsular infiltration using liposomal bupivacaine (LB) has been employed as an alternative analgesic approach. METHODS: This retrospective study compared outcomes for three analgesic approaches: femoral nerve catheter (FNC), adductor canal catheter (ACC), and intraoperative LB infiltration. The primary outcome was numeric rating scale (NRS) pain scores at 24 hours. Secondary outcomes included pain scores at 12, 36, and 48 hours, time-to-first opioid, cumulative opioid use, distance walked, and time-to-discharge. RESULTS: Pain scores at 24 hours were significantly lower in both the ACC and FNC cohorts when compared to the LB cohort (3.1 versus 4.6 [P = .017] and 2.4 versus 4.6 [P < .0001]). The ACC and FNC groups did not differ significantly at that timepoint (P = .27). Similar comparisons were found at 12 and 36 hours, while at 48 hours the FNC group was superior. Time to first opioid and opioid consumption favored the ACC and FNC groups. Walking distance favored the ACC group. Both the ACC and LB groups had a faster time-to-discharge than the FNC group. CONCLUSION: Both ACCs and FNCs provided superior analgesia at 24 hours compared to LB, while being equivalent to each other. Pain scores at 12 hours and 36 hours as well as opioid consumption through 48 hours mirrored this finding. Although various differences were found between groups in terms of time-to-first analgesic, walking distance and time-to-discharge, the ACC approach appeared to optimally balance analgesia, ambulation, and time-to-discharge.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis.

OBJECTIVES: To 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). METHODS: SLR 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. RESULTS: Fifty-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. CONCLUSION: The 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.

Outcomes of children born to mothers with systemic lupus erythematosus exposed to hydroxychloroquine or azathioprine.

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.

The BILAG-2004 index is associated with development of new damage in SLE.

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.

Randomized controlled trial of intrathecal oxytocin on speed of recovery after hip arthroplasty.

ABSTRACT: Recovery from surgery is quicker in the postpartum period, and this may reflect oxytocin action in the spinal cord. We hypothesized that intrathecal injection of oxytocin would speed recovery from pain and disability after major surgery. Ninety-eight individuals undergoing elective total hip arthroplasty were randomized to receive either intrathecal oxytocin (100 µg) or saline. Participants completed diaries assessing pain and opioid use daily and disability weekly, and they wore an accelerometer beginning 2 weeks before surgery until 8 weeks after. Groups were compared using modelled, adjusted trajectories of these measures. The study was stopped early due to the lack of funding. Ninety patients received intrathecal oxytocin (n = 44) or saline (n = 46) and were included in the analysis. There were no study drug-related adverse effects. Modelled pain trajectory, the primary analysis, did not differ between the groups, either in pain on day of hospital discharge (intercept: -0.1 [95% CI: -0.8 to 0.6], P = 0.746) or in reductions over time (slope: 0.1 pain units per log of time [95% CI: 0-0.2], P = 0.057). In planned secondary analyses, postoperative opioid use ended earlier in the oxytocin group and oxytocin-treated patients walked nearly 1000 more steps daily at 8 weeks ( P < 0.001) and exhibited a clinically meaningful reduction in disability for the first 21 postoperative days ( P = 0.007) compared with saline placebo. Intrathecal oxytocin before hip replacement surgery does not speed recovery from worst daily pain. Secondary analyses suggest that further study of intrathecal oxytocin to speed functional recovery without worsening pain after surgery is warranted.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.