Plain Language Summary of the PAISLEY study: deucravacitinib as a treatment for people with systemic lupus erythematosus.

What is this summary about?This plain language summary describes the results of the phase 2 study called PAISLEY which tested deucravacitinib, a new medicine under investigation before approval, in people living with lupus. In this trial, researchers wanted to find out if deucravacitinib would be safe and reduce the symptoms and disease activity in people living with lupus. PAISLEY looked at the type of lupus known as systemic lupus erythematosus, shortened to SLE.What happened in the study?The study included 363 people from 17 countries who had SLE and were between 18 and 75 years of age. The participants were divided into 4 groups at random. One group was given placebo (a fake or dummy pill that contains no medicine) and the other 3 groups took deucravacitinib, a pill taken by mouth. Each of the groups taking deucravacitinib took a different dose, either 3 milligrams (mg) twice daily, 6 mg twice daily, or 12 mg once daily. After 32 and 48 weeks, researchers measured the number of people in each group who had improvements in their SLE symptoms and disease activity, as measured by different tests. They also looked at any side effects people experienced, which may or may not have been caused by the medicine.What do the results mean?After 32 weeks of treatment, SLE symptoms and disease activity improved in more people in each of the deucravacitinib dose groups compared with the people taking placebo (the dummy pill). After 48 weeks of treatment, SLE symptoms and disease activity were still improved in more people taking deucravacitinib compared with people taking placebo, and this was measured in several different ways. The best results were seen in people taking deucravacitinib 3 mg twice daily. The number of serious side effects was similar for people taking deucravacitinib and those taking placebo. The most common side effects that were seen in people taking deucravacitinib were infections such as sore throat, cough, or bronchitis (upper respiratory tract), infltion in the nose (nasopharyngitis), headaches, and urinary tract infections. More people taking deucravacitinib than placebo had acne, rash, and cold sores (oral herpes). These were not serious and did not have any long-term effects on patient health or lead to patients stopping treatment.How to say (double click sound icon to play sound)… Systemic lupus erythematosus: SIS-teh-MIC LOO-puhs Eh-RE-the-ma-TOE-susDeucravacitinib: doo-KRAV-a-sih-ti-nibEnzyme: EN-zimeInterferon: in-tur-FER-onPlacebo: pluh-SEE-bohTyrosine kinase: TY-ruh-seen KY-naysTYK2: TIK-tu.

Alcohol and drug use severity are independently associated with antiretroviral adherence in the current treatment era.

Substance use in people with HIV (PWH) negatively impacts antiretroviral therapy (ART) adherence. However, less is known about this in the current treatment era and the impact of specific substances or severity of substance use. We examined the associations of alcohol, marijuana, and illicit drug use (methamphetamine/crystal, cocaine/crack, illicit opioids/heroin) and their severity of use with adherence using multivariable linear regression in adult PWH in care between 2016 and 2020 at 8 sites across the US. PWH completed assessments of alcohol use severity (AUDIT-C), drug use severity (modified ASSIST), and ART adherence (visual analogue scale). Among 9400 PWH, 16% reported current hazardous alcohol use, 31% current marijuana use, and 15% current use of ≥1 illicit drugs. In multivariable analysis, current methamphetamine/crystal use, particularly common among men who had sex with men, was associated with 10.1% lower mean ART adherence (p < 0.001) and 2.6% lower adherence per 5-point higher severity of use (ASSIST score) (p < 0.001). Current and more severe use of alcohol, marijuana, and other illicit drugs were also associated with lower adherence in a dose-dependent manner. In the current HIV treatment era, individualized substance use treatment, especially for methamphetamine/crystal, and ART adherence should be prioritized.

A Phase I Trial of the ABCB1 Inhibitor, Oral Valspodar, in Combination With Paclitaxel in Patients With Advanced Solid Tumors.

OBJECTIVES: Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. METHODS: Patients were treated with single-agent paclitaxel Q3W 175 mg/m 2 (or 135 mg/m 2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m 2 ), 40% (70 mg/m 2 ), or 50% (87.5 mg/m 2 ) of 175 mg/m 2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. RESULTS: Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. CONCLUSION: Paclitaxel at 70 mg/m 2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.

The Nature of Theory Used in Practice Education: A Scoping Review.

Background. Placements are key contexts for occupational therapy students to connect theoretical knowledge (theory) with practice. Theory relates to the prevailing ideas and concepts used by a profession. It can be derived within and outside the profession (discipline-specific knowledge and related knowledge, respectively). Purpose. This scoping review aimed to identify what is known about the nature of theoretical knowledge used in occupational therapy practice education. Method. A search of 4 electronic databases identified 19 relevant publications, data from which was extracted deductively. Findings. Inconsistent descriptions related to discipline-specific knowledge while related knowledge was often presented as not integrated with, or complementing, discipline-specific knowledge. Some authors referred to educational knowledge and methods informing student's theory use during placements. Implications. Educational methods need to provide a foundational platform, enabling novice learners to structure their thinking about ways discipline-specific and related knowledge can be used within an occupational framework on placement.

New Graduates' Experiences in Paediatric Private Practice: Learning to Make Intervention Decisions.

Background. Challenges with clinical decision-making are common among new graduate occupational therapists. There is limited research exploring their experiences of learning to make intervention decisions. Purpose. To explore new graduates' experiences of learning to make intervention decisions in pediatric private practice. Method. A case study approach, involving a range of data sources, explored the experiences of 11 new graduates and three experienced occupational therapists working in Australian private practices. Data were analyzed using inductive thematic analysis. Findings. Themes pervading new graduates' decision-making experiences were: "being seen as capable and competent," "similar and familiar," and "specialist versus generalist positions." Contextual influences contributed to new graduates utilizing their support networks and personal experiences in addition to workplace supports. Implications. It is vital to balance private practice business demands with opportunities for new graduates to engage with experienced occupational therapists and professional communities of practice to assist their learning to make intervention decisions.

The Clinical Challenges Experienced by New Graduate Occupational Therapists: A Matrix Review.

BACKGROUND.: The transition from student to new graduate occupational therapist is recognized as stressful. Current literature has not specifically drawn together the challenges new graduates face when learning to work with clients. PURPOSE.: This review aimed to synthesize common challenges that new graduate occupational therapists face when working with clients. METHODS.: Searches of online scholarly databases located research articles. Content related to working with clients in practice was charted using the Matrix Method. FINDINGS.: From 21 articles, four categories of challenges were identified: "reasoning and decision-making," "using knowledge and skills in practice with clients," "the context of service provision," and "managing caseload and priorities." "Having self-doubt" was a theme that pervaded the data. IMPLICATIONS.: New graduates often do not feel fully prepared for all aspects of occupational therapy practice. As they may not have access to substantial workplace support, exploring personal resources and professional support may assist this challenging transition.

Correction to: Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG).

The last author's first name was truncated in the initial online publication. The original article has been corrected.

Phase I-II trial of imatinib mesylate (Gleevec; STI571) in treatment of recurrent oligodendroglioma and mixed oligoastrocytoma. North central cancer treatment group study N0272 (ALLIANCE/NCCTG).

PURPOSE: To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors. METHODS: Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600 mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2-stage design was utilized, with 90% power to detect PFS6 increase from 25 to 45%. RESULTS: In the Phase I, maximum tolerated dose was not reached at 1200 mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0 months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0 months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2 months, HR = 0.43, 95% CI 0.21,0.89, p = 0.019). Confirmed response rate was 3.9% (PR = 1; REGR = 1), with stable disease observed in 52.9%. At 600 mg/D, mean steady-state imatinib plasma concentration was 2513 ng/ml (95% CI 1831,3195). Grade 3-4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%. CONCLUSIONS: Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated patients than controls, this finding would require forward validation in a larger cohort. Imatinib might show greater activity in a population enriched for PDGF-dependent pathway activation in tumor tissue.

Quantifying stratosphere-troposphere transport of ozone using balloon-borne ozonesondes, radar windprofilers and trajectory models.

In a series of 10-day campaigns in Ontario and Quebec, Canada, between 2005 and 2007, ozonesondes were launched twice daily in conjunction with continuous high-resolution wind-profiling radar measurements. Windprofilers can measure rapid changes in the height of the tropopause, and in some cases follow stratospheric intrusions. Observed stratospheric intrusions were studied with the aid of a Lagrangian particle dispersion model and the Canadian operational weather forecast system. Definite stratosphere-troposphere transport (STT) events occurred approximately every 2-3 days during the spring and summer campaigns, whereas during autumn and winter, the frequency was reduced to every 4-5 days. Although most events reached the lower troposphere, only three events appear to have significantly contributed to ozone amounts in the surface boundary layer. Detailed calculations find that STT, while highly variable, is responsible for an average, over the seven campaigns, of 3.1% of boundary layer ozone (1.2 ppb), but 13% (5.4 ppb) in the lower troposphere and 34% (22 ppb) in the middle and upper troposphere, where these layers are defined as 0-1 km, 1-3 km, and 3-8 km respectively. Estimates based on counting laminae in ozonesonde profiles, with judicious choices of ozone and relative humidity thresholds, compare moderately well, on average, with these values. The lamina detection algorithm is then applied to a large dataset from four summer ozonesonde campaigns at 18 North American sites between 2006 and 2011. The results show some site-to-site and year-to-year variability, but stratospheric ozone contributions average 4.6% (boundary layer), 15% (lower troposphere) and 26% (middle/upper troposphere). Calculations were also performed based on the TOST global 3D trajectory-mapped ozone data product. Maps of STT in the same three layers of the troposphere suggest that the STT ozone flux is greater over the North American continent than Europe, and much greater in winter and spring than in summer or fall. When averaged over all seasons, magnitudes over North America show similar ratios between levels to the previous calculations, but are overall 3-4 times smaller. This may be because of limitations (trajectory length and vertical resolution) to the current TOST-based calculation.

Am I Being Understood? Veterinary Students' Perceptions of the Relationship between Their Language Background, Communication Ability, and Clinical Learning.

During clinical workplace learning, effective communication between veterinary students and clinical staff is of paramount importance to facilitating learning, assessment, and patient care. Although studies in health sciences education have indicated that students may experience communication difficulties as a result of linguistic, cultural, and other factors and that these difficulties can affect clinical learning and academic outcomes, this has not yet been explored in veterinary clinical educational contexts. In this study, the authors sought to identify whether final-year veterinary students perceived that their communication ability influenced their clinical learning and, if so, whether language background was of significance. Seventy-one students from a final-year cohort at an Australian veterinary school completed a student perception survey at the end of their clinical training. Exploratory factor analysis was used to investigate the extent to which learners perceived that their communication ability influenced their clinical learning. Two factors explained 72.3% of total variance. Factor 1 related to communication ability as a source of concern; Factor 2 related to comprehending and contributing to clinical conversations. Communication ability as a source of concern differed significantly ( p < .001) between students who did and did not have an English-speaking background, but there was no significant difference between these two student groups for Factor 2. Although language background was associated with self-perceived communication ability, evidence also emerged that students may experience communication challenges during clinical learning, irrespective of their language background.

Streptococcal Endo-ß-N-Acetylglucosaminidase Suppresses Antibody-Mediated Inflammation In Vivo.

Endo-ß-N-acetylglucosaminidase (EndoS) is a family 18 glycosyl hydrolase secreted by Streptococcus pyogenes. Recombinant EndoS hydrolyzes the ß-1,4-di-N-acetylchitobiose core of the N-linked complex type glycan on the asparagine 297 of the γ-chains of IgG. Here, we report that EndoS and IgG hydrolyzed by EndoS induced suppression of local immune complex (IC)-mediated arthritis. A small amount (1 µg given i.v. to a mouse) of EndoS was sufficient to inhibit IgG-mediated arthritis in mice. The presence of EndoS disturbed larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen-antibody binding per se were affected. Thus, EndoS could potentially be used for treating patients with IC-mediated pathology.

Study of Flare Assessment in Systemic Lupus Erythematosus Based on Paper Patients.

OBJECTIVE: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus. METHODS: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity. RESULTS: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features. CONCLUSION: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

Collagen Autoantibodies and Their Relationship to CCP Antibodies and Rheumatoid Factor in the Progression of Early Rheumatoid Arthritis.

Serum autoantibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) are important markers for diagnosis and prognosis of rheumatoid arthritis (RA), but their autoantigens are not cartilage-specific. Autoantibodies to joint-specific type II collagen (CII) also occur in RA, and monoclonal antibodies of similar specificity induce collagen antibody-induced arthritis in animals, but their role in RA is uncertain. We utilized an enzyme-linked immunosorbent assay (ELISA) with the CB10 peptide of CII to compare the frequency of autoantibodies with those of anti-CCP and RF in stored sera from a prospective study of 82 patients with early RA to examine the outcome, defined as remission (n = 23), persisting non-erosive arthritis (n = 27), or erosions (n = 32). Initial frequencies of anti-CB10, anti-CCP and RF were 76%, 54%, and 57% in RA, and 4%, 0%, and 9% in 136 controls. The frequency of anti-CB10 was unrelated to outcome, but anti-CCP and RF increased with increasing severity, and the number of autoantibodies mirrored the severity. We suggest RA is an immune complex-mediated arthritis in which the three antibodies interact, with anti-CII inducing localized cartilage damage and inflammation resulting in citrullination of joint proteins, neoepitope formation, and a strong anti-CCP response in genetically-susceptible subjects, all amplified and modified by RF.

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.

OBJECTIVE: To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. METHODS: The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. RESULTS: 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. CONCLUSIONS: In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

Prenatal exposure to soy and selenium reduces prostate cancer risk factors in TRAMP mice more than exposure beginning at six weeks.

BACKGROUND: Diets high in soy and selenium (Se) decrease prostate cancer risk factors in healthy rats. The purpose of this study was to determine whether treatment with high levels of soy and/or supplemental Se would decrease prostate cancer risk factors in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse, and whether timing of the introduction of these nutrients would affect risk reduction. METHODS: Male hemizygous [C57BL/6 × FVB]F1 TRAMP mice were exposed to stock diets high or devoid of soy, with or without a supplement of Se-methylselenocysteine (MSC) starting at conception (10 mg Se/L in drinking water of pregnant/nursing dams; daily bolus of 4 mg Se/kg body weight to pups after weaning) or at 6 weeks of age in a 2 × 2 factorial design. Mice were killed at 12 weeks (n per dietary treatment = 20-30). RESULTS: Liver and serum Se concentrations were increased by MSC supplementation (P < 0.001), high-soy diet (P < 0.05), and initiation of dietary treatments at conception (P < 0.05). MSC supplementation had greater effects in mice fed the zero-soy basal diet, compared to the high-soy formulation (Pinteraction < 0.01). These same three interventions, individually and interactively, decreased body weight and epididymal fat pad weights, and steady state levels of mRNA for Cyp19a1 (aromatase) and Srd5a1 (5α-reductase). In contrast, MSC was the only treatment that decreased urogenital tract weights (P < 0.001), serum IGF-1 levels (P < 0.002), and Gleason scores (P < 0.05). CONCLUSIONS: Supplemental MSC reduces risk of prostate cancer in TRAMP mice. Basal diet composition (zero- vs. high-soy) can modify MSC's chemopreventive effects. Initiation of dietary treatments from conception maximizes chemopreventive effects of MSC. Prenatal Se status may have long-lasting effects on development and progression of prostate cancer.

Long-Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate-to- Severe Systemic Lupus Erythematosus: Results From an Open-Label Extension Study.

OBJECTIVE: The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). METHODS: Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. RESULTS: A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. CONCLUSION: Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). METHODS: This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. RESULTS: Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. CONCLUSION: SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. TRIAL REGISTRATION NUMBER: NCT01205438.