Differences in treatment response between female and male psoriatic arthritis patients during IL-12/23 therapy with or without methotrexate: post hoc analysis of results from the randomised MUST trial.

BACKGROUND: The influence of sex on treatment outcomes during interleukin-12/23 therapy in patients with psoriatic arthritis (PsA) has not been explored. OBJECTIVE: To conduct exploratory post hoc analyses of sex-stratified data from the MUST trial, an investigator-initiated, multicentre, phase 3b study in which patients with active PsA initiating treatment with open-label ustekinumab were randomised to treatment with placebo or methotrexate (MTX). METHODS: We evaluated baseline characteristics, key treatment outcomes and adverse events stratified by sex, with a focus on outcomes that did not include erythrocyte sedimentation rate (ESR) as a component due to the known elevation of ESR in females. RESULTS: A total of 166 patients were treated with ustekinumab+MTX (37 female, 50 male) or ustekinumab+placebo (32 female, 47 male). At baseline, females had a significantly longer time since PsA diagnosis and greater impairment in physical function, but similar joint counts. At week 24, both females and males showed marked improvements to ustekinumab with or without MTX. Females generally had numerically reduced treatment responses compared with males, although differences did not achieve statistical significance. MTX did not show an overall effect on treatment outcomes, but was associated with faster enthesitis responses in males only. Adverse events were generally comparable, but females in the ustekinumab+MTX group had higher levels of gastrointestinal disorders. CONCLUSION: Females and males with PsA had differences in baseline characteristics, treatment responses and adverse events during therapy. A better understanding of sex-based differences in PsA may help optimise treatment.

Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial.

BACKGROUND: The role of methotrexate in combination with biological agents in patients with psoriatic arthritis remains unclear. The MUST phase 3b trial aimed to compare the efficacy of ustekinumab plus placebo with ustekinumab plus methotrexate in patients with active psoriatic arthritis. METHODS: In this investigator-initiated, randomised, multicentre, placebo-controlled, phase 3b non-inferiority trial done in 22 centres in Germany, patients with active psoriatic arthritis received open-label ustekinumab and were randomly assigned (1:1) to masked concomitant therapy with placebo or methotrexate (ongoing or new). The primary outcome was non-inferiority of mean Disease Activity Score-28 joints (DAS28) at week 24 for ustekinumab monotherapy (ustekinumab plus placebo) versus ustekinumab combination therapy (ustekinumab plus methotrexate), stratified by previous methotrexate treatment. The key secondary analysis was non-inferiority of DAS28 at week 52. The primary analysis was based on a stratified van Elteren test with an α of 2·5% and a non-inferiority margin of 12·5% by Mann-Whitney estimator. Adverse events and serious adverse events were assessed. This study is registered with ClinicalTrials.gov, NCT03148860. FINDINGS: Between Jan 24, 2017, and April 12, 2021, 186 patients with active psoriatic arthritis were screened, of whom 173 (93%) patients were enrolled and randomly assigned (1:1) to receive concomitant methotrexate therapy (n=88) or placebo (n=85). 84 patients were receiving methotrexate at baseline, and 89 patients had no previous methotrexate treatment. 166 (96%) patients (87 in the ustekinumab plus methotrexate group and 79 in the ustekinumab plus placebo group) were included in the safety and efficacy analyses at week 24 (69 [42%] female; 97 [58%] male; mean age 48·2 years [SE 1·1]). Ustekinumab plus placebo was non-inferior to ustekinumab plus methotrexate in DAS28 at week 24 (2·9 [SD 1·31] vs 3·1 [1·42]); the stratified Mann-Whitney estimator for treatment comparison was 0·5426 (95% CI 0·4545-0·6307). Non-inferiority for ustekinumab plus placebo was also observed in DAS28 at week 52. Serious adverse events occurred in seven (9%) patients in the ustekinumab plus placebo group and eight (9%) patients in the ustekinumab plus methotrexate group. No specific serious adverse events affected more than one patient, and there were no deaths. INTERPRETATION: Interleukin (IL)-12 and IL-23 inhibition with ustekinumab is an effective treatment for psoriatic arthritis independent of methotrexate use; concomitant methotrexate did not increase efficacy of ustekinumab (based on DAS28). On the basis of these data, there is no evidence to support the addition or maintainance of methotrexate when initiating ustekinumab in patients with active psoriatic arthritis. FUNDING: Janssen Cilag.

Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

BACKGROUND: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. METHODS: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. RESULTS: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. CONCLUSIONS: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Combining Minimally Invasive Surgery With Ultra-Fast-Track Anesthesia in HeartMate 3 Patients: A Pilot Study.

BACKGROUND: Minimally invasive surgery for left ventricular assist device implantation may have advantages over conventional sternotomy (CS). Additionally, ultra-fast-track anesthesia has been linked to better outcomes after cardiac surgery. This study summarizes our early experience of combining minimally invasive surgery with ultra-fast-track anesthesia (MIFTA) in patients receiving HeartMate 3 devices and compares the outcomes between MIFTA and CS. METHODS: From October 2015 to January 2019, 18 of 49 patients with Interagency Registry for Mechanically Assisted Circulatory Support profiles >1 underwent MIFTA for HeartMate 3 implantation. For bias reduction, propensity scores were calculated and used as a covariate in a regression model to analyze outcomes. Weighted parametric survival analysis was performed. RESULTS: In the MIFTA group, intensive care unit stays were shorter (mean difference, 8 days [95% CI, 4-13]; P<0.001), and the incidences of pneumonia and right heart failure were lower than those in the CS group (odds ratio, 1.36 [95% CI, 1.01-1.75]; P=0.016, respectively). At 6 and 12 hours postoperatively, MIFTA patients had a better hemodynamic performance with lower pulmonary wedge pressure (mean difference, 2.23 mm Hg [95% CI, 0.41-4.06]; P=0.028) and a higher right ventricular stroke work index (mean difference, -1.49 g·m/m2 per beat [95% CI, -2.95 to -0.02]; P=0.031). CS patients had a worse right heart failure-free survival rate (hazard ratio, 2.35 [95% CI, 0.96-5.72]; P<0.01). CONCLUSIONS: Compared with CS, MIFTA is a beneficial approach for non-Interagency Registry for Mechanically Assisted Circulatory Support 1 HeartMate 3 patients with lower adverse event incidences, better hemodynamic performance, and preserved right heart function. Future large multicentric investigations are required to verify MIFTA's effects on outcomes.

The gut hormone glucose-dependent insulinotropic polypeptide is downregulated in response to myocardial injury.

BACKGROUND: The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its metabolic function GIP has been found to exhibit direct cardio- and atheroprotective effects in mice and to be associated with cardiovascular prognosis in patients with myocardial infarction. The aim of this study was to characterize endogenous GIP levels in patients with acute myocardial infarction. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented with clinical indication of coronary angiography. Circulating GIP levels were significantly lower in patients with STEMI (ST-elevation myocardial infarction; n=100) compared to clinically stable patients without myocardial infarction (n=631) (216.82 pg/mL [Q1-Q3: 52.37-443.07] vs. 271.54 pg/mL [Q1-Q3: 70.12-542.41], p = 0.0266). To characterize endogenous GIP levels in patients with acute myocardial injury we enrolled 18 patients scheduled for cardiac surgery with cardiopulmonary bypass and requirement of extracorporeal circulation as a reproducible condition of myocardial injury. Blood samples were drawn directly before surgery (baseline), upon arrival at the intensive care unit (ICU), 6 h post arrival to the ICU and at the morning of the first and second postoperative days. Mean circulating GIP concentrations decreased in response to surgery from 45.3 ± 22.6 pg/mL at baseline to a minimum of 31.9 ± 19.8 pg/mL at the first postoperative day (p = 0.0384) and rose again at the second postoperative day (52.1 ± 28.0 pg/mL). CONCLUSIONS: Circulating GIP levels are downregulated in patients with myocardial infarction and following cardiac surgery. These results might suggest nutrition-independent regulation of GIP secretion following myocardial injury in humans.

Fluorescence-optical imaging as a promising easy-to-use imaging biomarker to increase early psoriatic arthritis detection in patients with psoriasis: a cross-sectional cohort study with follow-up.

OBJECTIVES: To evaluate the ability of fluorescence-optical imaging (FOI) to detect preclinical musculoskeletal inflammatory signs in patients with skin psoriasis at risk of developing psoriatic arthritis (PsA). METHODS: This investigator-initiated prospective exploratory study evaluated adult patients with psoriasis with musculoskeletal complaints and/or nail psoriasis within the last 6 months. Patients underwent a comprehensive rheumatological clinical examination (CE) along with musculoskeletal ultrasound (MSUS) and FOI of both hands at a single visit. Patients with CE-/MSUS-/FOI+ findings had MRI performed on the symptomatic or dominant hand within 7 days. If MRI was negative, the patients were followed over 2 years for the onset of clinically manifest PsA. RESULTS: A total of 389 patients were referred from dermatology centres and evaluated at 14 rheumatology sites in Germany. Seventy-seven (20%) patients with CE-/US-/FOI- were considered to have psoriasis only. PsA was diagnosed in 140/389 patients (36%) based on CE alone and in another 55 patients (14%) by additional MSUS; overall, 50% of the patient cohort was diagnosed with PsA. One hundred sixteen patients (30%) were FOI+ (CE-) of which 40 (37%) were FOI+/MRI+. In the 2-year follow-up of the FOI+/CE- patients, clinical PsA was confirmed in another 12%. CONCLUSION: FOI is a promising method for the detection of signs of musculoskeletal inflammation in hands that may serve as an early imaging biomarker for transitions from psoriasis to PsA. This imaging technique has the potential to detect PsA in at-risk patients with psoriasis, reduce time to PsA diagnosis and improve patient outcomes.

Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction.

AIMS: Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. METHODS AND RESULTS: In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. CONCLUSION: In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.