Elevated Creatine Phosphokinase Research Articles

Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma.

Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.

A145 EFFICACY AND SAFETY OF UPADACITINIB MAINTENANCE THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM A RANDOMIZED PHASE 3 STUDY

BackgroundUpadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials.AimsEvaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials.MethodsThe primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI).ResultsBaseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%).ConclusionsIn patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed.Funding AgenciesAbbVie

Relation between Serum Creatine Phosphokinase Levels and Acute Kidney Injury among ST-Segment Elevation Myocardial Infarction Patients.

Background: Among patients with rhabdomyolysis, the leakage of intracellular skeletal muscle content such as creatine phosphokinase (CPK) into the bloodstream has been associated with an increased risk of acute kidney injury (AKI). We evaluated the possible relationship between serum CPK levels and AKI occurrence among patients with myocyte injury secondary to ST-elevation myocardial infarction (STEMI). Methods: We retrospectively included 2794 patients with STEMI. Patients were stratified according to peak serum CPK levels into mild (<1000 U/L, n = 1603), moderate (1000–5000 U/L, n = 1111), and severe (>5000 U/L, n = 80) categories. The occurrence of AKI was defined by the KDIGO criteria as an increase in serum creatinine (sCR) ≥0.3 mg/dL within 48 h following PCI. The predictive value of CPK for the risk of AKI occurrence was assessed using multivariate logistic regression models. Results: The overall occurrence of AKI was 10.4%. Incidence of AKI showed a gradual increase between patients with mild, moderate, and severe serum CPK level elevations (7.8% vs. 11% vs. 26% respectively; p < 0.001). In multivariate logistic regression models, both moderate or higher (OR 1.6, 95% CI 1.1–2.2; p = 0.01) and severe (OR 2.8 95% CI 1.4–5.6; p = 0.004) serum CPK level elevations were independently associated with AKI. Conclusions: Among STEMI patients, elevated CPK levels were associated with AKI. This association is presumably independent; however, it remains unclear whether it is due to direct toxic (myoglobin-related) or hemodynamic effects (poor left ventricular function). Further studies are required to reveal the underlying mechanism.

The Correlation of Lipid Peroxidation and Antioxidant Capacity on Perioperative Outcomes in On-Pump CABG in Adults.

Background: Cardiac surgeries in adults usually use cardiopulmonary bypass (CPB) for cardiac protection and provide a blood-free field for operation. However, due to changes in tissue perfusion and ischemia-reperfusion injury (IRI), there are some side effects for CPB operations. Lipid peroxidation and compromised antioxidant defense are consequences of IRI. This can, in turn, cause organ dysfunction and lead to unwanted biochemical and clinical changes. Methods: In a cross-sectional study 107 patients with the ages of 35 to 79 years old matching the inclusion criteria with indication for elective on-pump CABG were studied. Renal function, serum malondialdehyde (MDA) and total antioxidant capacity (TAC), and clinical outcomes were studied until 24 hours after intensive care unit (ICU) admission. Correlations between MDA and TAC and other outcomes were tested. Between-group comparisons was one-way ANOVA with repeated measures was used for inferring changes in the plasma TAC and MDA levels, creatinine, and BUN over time. Correlations were investigated using regression models. Results: Preoperative EF was inversely correlated with TAC at post- CPB time (r= -0.262, p= 0.031). Hyperlipidemia (HLP) was directly associated with higher MDA at post- CPB time (r= 0.267, p= 0.017. Cross-clamp and CPB duration were inversely correlated with the systemic MDA concentration at 24 hours post-ICU admission (r= -0.314, p= 0.005 and r= -0.312, p= 0.005, respectively). Preoperative TAC was inversely correlated with lactate at ICU admission (r= -0.294, p= 0.011). Creatine phosphokinase (CPK) and TAC were directly correlated with post-CPB time (r= -0.327, p= 0.006). Conclusion: According to the findings, a direct correlation between TAC and myocardial protection during CPB exists. Reduced TAC during CPB is associated with elevation of muscle damage marker CPK. Preoperative HLP is associated with higher circulatory MDA content at the post-CPB time.

P573 The safety profile of upadacitinib maintenance therapy in ulcerative colitis in the Phase 3 U-ACHIEVE study is consistent with that in approved indications

Abstract Background The oral, small-molecule, selective and reversible Janus kinase inhibitor upadacitinib (UPA) is approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), moderate-to-severe atopic dermatitis (AD) and ankylosing spondylitis, and is under investigation in ulcerative colitis (UC). This assessment reviewed adverse event (AE) data for UPA maintenance therapy in UC in the context of the known long-term safety profile of UPA in its approved indications. Methods Safety data were collated from patients with UC who responded to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) and were enrolled in U-ACHIEVE to receive maintenance treatment (UPA 15 mg, 30 mg QD or placebo) for ≤52 weeks. Treatment-emergent AEs (TEAEs) were defined as AEs with an onset on or after the first dose, and ≤30 days after the last dose, of study drug. Safety data were also collected from two AD (15 and 30 mg doses), six RA (15 mg dose in all, 30 mg dose in four) and two PsA (15 and 30 mg doses) Phase 3 trials. Exposure-adjusted event rates were calculated for TEAEs and AEs of special interest (AESIs). Results Data were available for 746 patients with UC who received 8 weeks’ induction with UPA 45 mg and were randomised to maintenance treatment as follows: placebo, n=245; UPA 15 mg, n=250; UPA 30 mg, n=251. Rates of any AEs, serious AEs, severe AEs and AEs leading to treatment discontinuation were lower with both UPA doses versus placebo (Table 1). No deaths occurred. Rates of the above AE categories in patients with UC who received maintenance treatment with UPA 15 or 30 mg were within the ranges previously reported in AD, RA and PsA, apart from neutropenia (Table 1). AESI rates in UC were generally similar with UPA and placebo, except for higher rates of herpes zoster, creatine phosphokinase elevation, hepatic disorder, and venous thromboembolism (VTE), but lower rates of anaemia, with UPA (Table 2). Non-melanoma skin cancer was reported only with UPA 30 mg. One adjudicated major cardiovascular event was reported in each of the placebo and UPA 30 mg arms. VTE only occurred with UPA treatment (two events per arm). Based on the limited number of patients exposed, and apart from a higher VTE rate, AESI rates in the UC maintenance study were generally similar to those reported in patients receiving long-term treatment with UPA 15 or 30 mg QD in AD, RA or PsA. Conclusion The safety profile of UPA maintenance treatment in UC is consistent with that in its approved indications. Although VTE rates were higher in UC, background VTE risk is known to be increased in UC versus AD, RA and PsA. This review identified no new important safety risks.

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta-analysis.

The present systematic review and meta-analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use. We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies. Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR =2.55, 95% CI 1.78-3.64, P < .00001, I2 =0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR =1.89, 95% CI 1.06-3.35, P = .03, I2 = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81-74.37, P = .01, I2 =0%). The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis.

Benign acute childhood myositis: Factors associated with muscle symptoms and resolution.

Benign acute childhood myositis (BACM) is associated with several viral infections. The aim of this study was to evaluate the progression of myositis symptoms, laboratory findings and oseltamivir treatment in children with influenza- and non-influenza-associated BACM. Patients aged 0-18 years old, admitted to the pediatric emergency department in the seasonal influenza period between 2018 and 2020 were retrospectively analyzed. Patients with acute onset calf tenderness, pain, difficulty in walking and elevated serum creatine phosphokinase were included and were grouped according to influenza rapid test kit results as influenza (A and B) positive, and influenza negative. The time to symptom resolution, laboratory data and the oseltamivir treatment were compared between the groups. There were 94 patients (67 male, 27 female) with a mean age of 77 ± 22 months. Influenza A was detected in 21, influenza B in 27, and neither were detected in 46 patients. Time to symptom resolution of BACM was shorter in the influenza-positive patients than in influenza-negative patients (2.9 ± 1.4 days and 3.5 ± 1.5 days, respectively, P = 0.027). Oseltamivir did not reduce the symptom resolution time in influenza patients. All children had normal hemoglobin and platelet counts, elevated creatine phosphokinase and 76% of them had leukopenia. Neither clinical recurrence nor metabolic disease were reported. Symptoms of BACM tended to resolve slightly earlier in influenza-positive patients and the duration of symptoms was not affected by oseltamivir treatment.

Improvement in childhood limb-girdle muscular dystrophy with Ayurvedic management

The Limb-Girdle Muscular Dystrophies (LGMDs) include a heterogeneous group of disorders characterized by the progressive wasting and weakness of the proximal limb-girdle muscles. Sarcoglycanopathies are forms of LGMD that result from defect in the sarcoglycan complex. Ayurveda explains the condition in the line of Srotorodha (~obstructive pathology occurring in channels), especially at the Mamsa dhatu (~muscle tissue) level. This is the case report of an eight year old male child of autosomal recessive LGMD with no relevant family history. The patient was presented with gradual onset of proximal muscle weakness in all four limbs for two years along with pseudohypertrophy of bilateral calf muscles. He had elevated Creatine Phosphokinase (CPK) level and the genetic test findings revealed a homozygous missense variation in exon 2 of the SGCA gene. He visited the outpatient department of the tertiary Government Ayurveda Hospital and Ayurveda medications were administered along with dietary advices for two months followed by in-patient management for one month. There was a significant improvement in the clinical findings assessed by the Vignos scale of lower extremity and Barthel index along with reduction in the level of CPK value after three months of Ayurvedic management. Significant improvement in this short period of management substantiates the benefit of Ayurvedic medicines in the management of LGMD.

A rare presentation of Carnitine palmitoyltransferase II (CPT-2) deficiency with normal acylcarnitine profile in a 10-year-old boy with muscle weakness and bilateral hearing loss; a case report.

Carnitine palmitoyltransferase II (CPT-2) deficiency is a rare and autosomal recessive disorder of long-chain fatty acids oxidation. Here, we reported a 10-year-old boy with bilateral hearing loss and a myopathic form of CPT II deficiency, which was confirmed by a molecular genetic test. He was admitted to our hospital with unexplained headaches, vomiting, and fever. Furthermore, he developed seizures, muscle weakness, neck stiffness and pain, mild respiratory distress, and an icteric appearance. The laboratory test results also showed severely elevated lactate dehydrogenase levels (LDH) and creatine phosphokinase (CPK) levels. He also had an icteric appearance with unexplained indirect hyperbilirubinemia. Further examinations revealed a normal heart and liver without any neurological disorders. Muscle pathological examination reported normal pathology without neuromuscular and mitochondrial disorders and storage diseases. Finally, molecular test analysis with next-generation sequencing (NGS) revealed CPT-II deficiency fatty acid oxidation disorder. Furthermore, we identified a homozygous pathogenic variant in theADGRV1gene, c.15736C>T p. (Arg5246*), which suggests the Usher syndrome type 2C and the reason for sensorineural hearing loss in this case. Our finding indicates that CPT-II can be associated with multiple symptoms and clinical features. Therefore, evaluation of CPT-II deficiency with molecular test analysis may be helpful in cases with unexplained icteric appearance, muscle weakness, and rhabdomyolysis.

Tropical spastic paraparesis-like illness in an HIV-Infected child

Human T-cell leukemia virus type 1(HTLV-1) is the etiological agent responsible for the clinical entity of tropical spastic paraparesis/HTLV-1-associated myelitis (TSP/HAM). HTLV-1 and HIV-1, being related retroviruses, coinfection with both is a well-recognized phenomenon but rarely reported in children. We describe a 5-year-old boy with no previously known comorbidity who presented with bilateral lower-limb weakness and calf pain along with urinary retention. Imaging confirmed the presence of myelitis. Investigations showed elevated creatine phosphokinase(CPK) values suggestive of myositis. It was later learned that the parents of the child were on treatment for HIV infection. Antibodies for HIV were positive by ELISA, and in view of the clinical picture, probability of a TSP-like illness as the initial presentation of a hitherto undiagnosed HIV infection was considered. TSP/HAM is an important yet underrecognized cause of spinal disease, especially in HIV-infected individuals. Certain features such as elevated to normal CD4 counts, absence of significant sensory symptoms, and associated myositis may serve as subtle clues to underlying HTLV-1 infection.

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial Registration NumbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00410-z.

Upadacitinib Was Efficacious and Well-tolerated Over 30 Months in Patients With Crohn’s Disease in the CELEST Extension Study

The long-term efficacy and safety of upadacitinib was evaluated in an open-label extension (OLE) of a phase II, double-blind, randomized trial of patients with Crohn's disease. Patients who completed the 52-week study (CELEST) received upadacitinib in the CELEST OLE as follows: those who had received immediate-release upadacitinib 3, 6, or 12 mg twice daily or 24 mg once daily (QD) received extended-release upadacitinib 15 mg QD and those who had received immediate-release upadacitinib 12 or 24 mg twice daily as rescue therapy received extended-release upadacitinib 30 mg QD. If any patient initiating upadacitinib 15 mg QD in CELEST OLE lost response at or after week 4, the dose was escalated to upadacitinib 30 mg QD (dose-escalated group). Clinical, endoscopic, inflammatory and quality-of-life measures were assessed. A total of 107 CELEST study completers entered CELEST OLE. The proportion of patients with clinical remission 2.8/1.0 was maintained between week 0 and month 30 in all groups (month 30: 15 mg, 61%; 30 mg, 54%; dose-escalation, 55%). Endoscopic response was maintained in all groups (month 24: 68%, 67%, and 40%, respectively). The rates of adverse events (AEs), serious AEs, AEs leading to discontinuation, infections, serious infections, herpes zoster, and creatine phosphokinase elevation were higher with upadacitinib 30 mg vs 15 mg. Sustained long-term benefit at 30 months and further endoscopic improvements to month 24 were observed in patients with Crohn's disease receiving upadacitinib. Safety over 30 months was consistent with the known safety profile of upadacitinib. gov ID no: NCT02782663.

Cardioprotective effects of alpha-mangostin on doxorubicin-induced cardiotoxicity in rats.

The main adverse effect of doxorubicin is cardiotoxicity. Oxidative stress and apoptosis induction have been suggested as mechanisms involved in its cardiotoxicity. In this study, cardioprotective effects of alpha-mangostin against doxorubicin-induced cardiotoxicity have been investigated in rats. Forty-two rats were divided as follows: Control, doxorubicin (2mg/kg every 48 hr), alpha-mangostin (200 mg/kg), alpha-mangostin (50, 100, 200 mg/kg) + doxorubicin (2mg/kg every 48 hr), and vitamin E (200 IU/kg) + doxorubicin (2mg/kg every 48 hr). Alpha-mangostin was administered by gavage for 19 days, while doxorubicin (12 days) and vitamin E (19 days) were injected intraperitoneally. Doxorubicin decreased heart rate, increased electrocardiogram signal components duration and reduced systolic and diastolic arterial blood pressure, and caused histological damage in the heart of rats. Doxorubicin decreased heart weight and heart/body weight ratio, as well as elevated creatine phosphokinase isoenzyme and lactate dehydrogenase. Doxorubicin increased malondialdehyde, inflammatory biomarkers, and caspases 3 and 9 and decreased reduced glutathione content in heart tissue but co-administration of alpha-mangostin (100 mg/kg) restored all doxorubicin toxic effects. Results show that alpha-mangostin has protective effects against doxorubicin-induced cardiotoxicity by antioxidant, antiinflammatory, and antiapoptotic effects that may ameliorate doxorubicin cardiotoxicity in human chemotherapy without reduction in its anticancer effect.

Multicenter Cohort Study of Ceftaroline Versus Daptomycin for Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infection.

BackgroundObservational data suggest ceftaroline may be effective for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI), but comparative data with standard of care are limited. This analysis compares the outcomes of MRSA BSI treated with ceftaroline or daptomycin.MethodsMulticenter, retrospective, observational cohort study of adult patients with MRSA BSI from 2010 to 2017. Patients treated with ≥72 hours of ceftaroline or daptomycin were included. Those clearing BSI before study drug and those with a pneumonia source were excluded. The primary outcome was composite treatment failure, defined as 30-day mortality, BSI duration ≥7 days on study drug, and 60-day MRSA BSI recurrence. Inverse probability of treatment weighted risk difference in composite failure between daptomycin and ceftaroline groups was computed and 15% noninferiority margin applied.ResultsTwo hundred seventy patients were included; 83 ceftaroline and 187 daptomycin. Ceftaroline was noninferior to daptomycin with respect to composite failure (39% daptomycin, 32.5% ceftaroline; weighted risk difference, 7.0% [95% confidence interval, –5.0% to 19.0%]). No differences between treatment groups was observed for 30-day mortality or other secondary efficacy outcomes. Creatine phosphokinase elevation was significantly more common among daptomycin patients (5.3% vs 0%, P = .034). Rash was significantly more common among ceftaroline patients (10.8 vs 1.1%, P = .001).ConclusionsNo difference in treatment failure or mortality was observed between MRSA BSI treated with ceftaroline or daptomycin. These data support future study of ceftaroline as a primary MRSA BSI treatment and current use of ceftaroline when an alternative to vancomycin and daptomycin is required.

A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis

BackgroundSystemic atopic dermatitis treatments that have acceptable safety are needed.ObjectiveTo evaluate the safety of the oral Janus kinase inhibitor upadacitinib in combination with topical corticosteroids (TCSs) for the treatment of atopic dermatitis.MethodsIn this phase 3, double-blind study (Rising Up), Japanese patients (12-75 years) with moderate-to-severe atopic dermatitis were randomized in a 1:1:1 ratio to receive 15 mg of upadacitinib + TCS, 30 mg of upadacitinib + TCS, or a placebo + TCS (rerandomized in a 1:1 ratio to receive either 15 or 30 mg of upadacitinib + TCS at week 16). Adverse events and laboratory data were assessed for safety.ResultsIn 272 treated patients, the serious adverse event rates were similar for 15- and 30-mg upadacitinib + TCS at week 24 (15 mg, 56%; 30 mg, 64%) but greater than those for placebo + TCS (42%). Acne (all mild or moderate; none leading to discontinuation) occurred more frequently with upadacitinib + TCS (15 mg, 13.2%; 30 mg, 19.8%) than with placebo + TCS (5.6%). Furthermore, herpes zoster infection (4.4% vs 0%), anemia (1.1% vs 0%), neutropenia (4.4% vs 1.1%), and creatine phosphokinase elevations (2.2% vs 1.1%) occurred more frequently with 30-mg upadacitinib + TCS than with 15-mg upadacitinib + TCS; none of these events were reported with placebo + TCS. No thromboembolic events, malignancies, gastrointestinal perforations, active tuberculosis, or deaths occurred.LimitationsThe limitations included a small sample size and short observation period as well as nongeneralizability of the results beyond Japanese populations.ConclusionsThe results were generally consistent with those of previous reports; no new safety risks were detected.

Upadacitinib as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs for psoriatic arthritis.

ObjectiveTo assess the efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA.MethodsPooled data were analysed from patients with prior inadequate response or intolerance to one or more nbDMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) who received placebo, UPA 15 mg once daily (QD) or UPA 30 mg QD as monotherapy or in combination with two or fewer nbDMARDs for 24 weeks. Efficacy outcomes included achievement of ACR responses, Psoriasis Area and Severity Index responses, minimal disease activity and change from baseline and clinically meaningful improvement in the HAQ Disability Index. Adverse events (AEs) were summarized.ResultsA total of 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects for a 20% improvement in ACR criteria at week 12 were 33.7% (95% CI 24.4, 43.1) and 34.0% (95% CI 27.9, 40.1) for UPA 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (95% CI 36.9, 54.5) and 39.6% (95% CI 33.7, 45.5) for UPA 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for UPA monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy.ConclusionThe efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of UPA with or without nbDMARDs in PsA.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov): SELECT-PsA 1 (NCT03104400), SELECT-PsA 2 (NCT03104374)

Baricitinib: The First Jak Inhibitor Approved in Europe for the Treatment of Moderate to Severe Atopic Dermatitis in Adult Patients.

Background: Atopic dermatitis (AD) is an inflammatory skin disease characterized by a wide phenotypic variety with a very complex pathophysiological mechanism that has led to the identification of new therapeutic targets, such as janus kinasis (JAK) inhibitors. Objectives: To evaluate the efficacy and safety of baricitinib, the first JAK 1 and 2 inhibitor approved in Europe for the treatment of adult patients with moderate-to-severe AD. Methods: The efficacy and safety data available from the Phase III studies belonging to the BREEZE AD program are presented. Results: Results from BREEZE-AD1, AD2, AD4, and AD7 showed the efficacy of Baricitib 4 mg, administered orally, once daily, as monotherapy or in combination with topical corticosteroid (TCS), with a significant proportion of patients achieving primary endpoints IGA 0–1 (16.4% vs. 4.8%; 13.8% vs. 4.5%; 21.7% vs. 9.7%; 30.6% vs. 14.7%) and EASI75 (24.8% vs. 8.8%; 21.1% vs. 6.1%; 31.5% vs. 17.2%; 47.7% vs. 22.9%) at week 16 (W16) compared to placebo, respectively. Baricitinib showed rapid improvement in symptoms, starting from week 1 of treatment at 4 mg dosage, with a good safety profile. Nasopharyngitis, upper respiratory tract infections (URIs), creatine phosphokinase (CPK) elevations, and headache were the most frequently reported adverse events. Conclusions: Following the efficacy and safety data on W 16 from the phase III BREEZE-AD studies, baricitinib has recently been approved in Europe for the treatment of moderate to severe AD in adult patients. Further data to evaluate long-term efficacy and safety in a real-life setting are needed.

Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability.

BackgroundIn this study, we investigated the risk factors for daptomycin-associated creatine phosphokinase (CPK) elevation and established a risk score for CPK elevation.MethodsPatients who received daptomycin at our hospital were classified into the non-elevated or elevated CPK group based on their peak CPK levels during daptomycin therapy. Univariable and multivariable analyses were performed, and a risk score and prediction model for the incidence probability of CPK elevation were calculated based on logistic regression analysis.ResultsThe non-elevated and elevated CPK groups included 181 and 17 patients, respectively. Logistic regression analysis revealed that concomitant statin use (odds ratio [OR], 4.45 [95% confidence interval {CI}, 1.40–14.47]; risk score 4), concomitant antihistamine use (OR, 5.66 [95% CI, 1.58–20.75]; risk score 4), and trough concentration (Cmin) between 20 and <30 µg/mL (OR, 14.48 [95% CI, 2.90–87.13]; risk score 5) and ≥30.0 µg/mL (OR, 24.64 [95% CI, 3.21–204.53]; risk score 5) were risk factors for daptomycin-associated CPK elevation. The predicted incidence probabilities of CPK elevation were <10% (low risk), 10%–<25% (moderate risk), and ≥25% (high risk) with total risk scores of ≤4, 5–6, and ≥8, respectively. The risk prediction model exhibited a good fit (area under the receiver operating characteristic curve, 0.85 [95% CI, .74–.95]).ConclusionsThese results suggested that concomitant use of statins with antihistamines and Cmin ≥20 µg/mL were risk factors for daptomycin-associated CPK elevation. Our prediction model might aid in reducing the incidence of daptomycin-associated CPK elevation.

Haff Disease in Salvador, Brazil, 2016-2021: Attack rate and detection of toxin in fish samples collected during outbreaks and disease surveillance

From late 2016 to early 2021, cases of Haff disease, a rare cause of rhabdomyolysis, possibly due to poisoning by palytoxin-like compounds in seafood, were detected in Salvador, Brazil. Surveillance was established to detect additional cases aiming at describing the clinical characteristics of the cases, identifying associated factors, estimating disease attack rate, and investigating the presence of biotoxins and trace metals in selected fish specimens obtained from cases. Between December/2016-January/2021, surveillance investigated Haff disease suspected cases, and obtained clinical and fish samples to test. Of 65 cases investigated during the 2016-2017 outbreak, 43 (66%) had high creatine phosphokinase (CPK) levels. Among those with laboratory-confirmed rhabdomyolysis, 38 (88%) were hospitalized, 11 (26%) required intensive care, and three (7%) dialysis. Ingestion of marine fish 24h before disease onset was reported by 74% of the cases with elevated CPK and by 41% of those without CPK measurement (P=0·02). Attack rate for individuals who ate fish related to the outbreak was 55%. Following this outbreak, surveillance identified 12 suspected cases between 2017-2019, and a second outbreak in 2020-2021, with 16 laboratory-confirmed rhabdomyolysis patients (five required intensive care; one died). No traces of ciguatoxins and metals were detected in fish specimens obtained in 2016, found to be Seriola rivoliana. Some fish samples from 2020 were screened for palytoxin (PlTX)-like compounds and contained detectable levels of molecule fragments characteristics of isobaric PlTX, ovatoxin-a (OVTX-a), OVTX-b and OVTX-d. These findings support the hypothesis that compounds related to PlTX accumulated in marine fish may be the toxic agent causing the disease. Haff disease is a life-threatening condition, requiring clinical suspicion for patients with sudden-onset myalgia following fish ingestion. Suspected cases should be reported to health authorities for investigation.

Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial

BackgroundCombination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)V600–mutated melanoma (IMMU-TARGET, NCT02902042). MethodsThe dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1 and 200 mg QD and 30 mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose of the triplet combination, DLT and safety. As per the sponsor's decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD,NCT04657991). ResultsFifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n = 1) and gamma glutamyl transferase (GGT) increase (n = 1). No DLT was observed in further 3 + 3 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III–IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12–45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35–87). At a median follow-up of 25 months (IQR, 9–28), progression-free survival at 12 months was 41% (95% CI, 13–68). ConclusionsTriplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control.