Elevated Creatine Phosphokinase Research Articles

Incidence and clinical predictors of left ventricular thrombus after ST elevation myocardial infarction as detected by magnetic resonance imaging

Abstract Funding Acknowledgements Type of funding sources: None. Background The aim of the current study was to characterize clinical predictors and to develop clinical risk score for left ventricular (LV) thrombus as detected by cardiac magnetic resonance imaging (CMR). Methods We evaluated 337 patients without known prior coronary disease, who underwent primary percutaneous coronary intervention for STEMI. All patients underwent transthoracic echocardiography (TTE) and CMR during their index hospitalization. We developed a novel prognostic risk model (ThrombScore) to identify patients at risk for LV thrombus development. Results Upon CMR, LV thrombus was present in 34 patients (10%), of whom 33 (97%) had an anterior wall MI and most (77%) had at least mildly reduced left ventricular ejection fraction (LVEF<45%) upon the first TTE. Sensitivity for thrombus formation of the first and second TTE was 5.9% and 59%, respectively. Multivariate logistic regression model revealed that elevated C reactive protein (CRP) levels, lack of ST-segment elevation (STe) resolution, elevated creatine phosphokinase (CPK) levels, and STe in anterior ECG leads are robust independent predictors of LV thrombus in STEMI patients. These variables were incorporated to construct the ThrombScore: a simple six-point risk model. The odds ratio for thrombus development per one-point increase in the score was 3.2 (95% Confidence Interval 2.1–5.01; p<0.001). Discrimination analysis of the model revealed c-statistics of 0.86 for thrombus development. The model identified three distinct risk categories (I, II and III) with thrombus incidence of 0%, 1.6% and 27.6%, respectively. Conclusions ThrombScore is a simple, practical, clinical risk model for risk stratification of thrombus formation in patients with STEMI.

Atypical Overlapping Features Complicating Diagnoses of Dysferlinopathy and Immune-Mediated Necrotizing Myopathy. (P6-8.006)

<h3>Objective:</h3> To present overlapping features and atypical characteristics of dysferlinopathy and immune-mediated necrotizing myopathy (IMNM). <h3>Background:</h3> Dysferlinopathy typically presents with early onset progressive muscle weakness that can be proximal or distal. Definitive diagnosis is made with DYSF gene testing. Treatment is supportive. IMNM is an autoimmune inflammatory myopathy that affects older individuals and is often associated with occult malignancy. Aggressive immunotherapy improves outcomes. Muscle biopsy (MBx) reveals inflammatory infiltrates in both conditions. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case 1:</h3> A 35-year-old man presented with subacute progressive limb weakness and elevated creatine phosphokinase (CPK) &gt;8,000 units/L. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining; dystrophy stains were omitted due to the patient’s age and subacute symptoms. Anti-signal recognition peptide (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies and malignancy screen were negative. The patient was initially diagnosed with seronegative IMNM and treated with steroids, methotrexate and IVIG without improvement. He was subsequently diagnosed with dysferlinopathy based on genetic testing showing double heterozygous pathogenic DYSF gene mutations. <h3>Case 2:</h3> An 18-year-old man presented with 3-years of progressive proximal limb weakness associated with Gower’s sign and elevated CPK &gt;10,000 units/L. Broad muscular dystrophy genetic testing was negative. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining suggestive of IMNM. Anti-SRP and anti-HMGCR antibodies, serum paraneoplastic panel, and malignancy screening with tumor markers, contrasted CT imaging, and scrotal ultrasound were negative. The patient was diagnosed with early-onset seronegative IMNM. CPK improved and symptoms stabilized with prednisone, methotrexate and IVIG therapy. <h3>Conclusions:</h3> Dysferlinopathy and IMNM can have overlapping clinical features and MBx findings. Heightened awareness of atypical features aids in timely diagnosis. Accurate diagnosis of dysferlinopathy based on genetic testing limits further invasive workup and the side effects of ineffective empiric therapy, whereas early diagnosis of IMNM allows for prompt immunotherapy which is shown to improve prognosis. <b>Disclosure:</b> Dr. Stout has nothing to disclose. Dr. Su has nothing to disclose.

Pregnancy course and outcomes of patients with polymyositis and dermatomyositis (PM/DM) managed in a single center

We aimed to determine the association between disease activity during pregnancy and pregnancy outcomes of women with polymyositis and dermatomyositis (PM/DM). Patients with PM/DM who were managed from pregnancy to delivery at Kagawa University Hospital from March 2006 to May 2021 were enrolled. Clinical data were retrospectively analyzed to evaluate the association between disease activity during pregnancy and pregnancy outcomes. Eight pregnancies in 5 women with PM/DM were analyzed. The mean age at conception was 28.3 ± 3.8 years, and mean disease duration was 6.3 ± 3.2 years. Four patients required an increased glucocorticoid dosage because of worsening disease activity (sustained elevation of creatine phosphokinase [CPK] concentration). Two patients who continuously received immunosuppressive drugs from conception to delivery showed no increase in disease activity and did not need increased glucocorticoid dosages. The pregnancy outcomes were 1 spontaneous abortion and 7 live births. The mean gestation length was 35.3 ± 5.2 weeks, and mean birthweight was 2297.7 ± 1041.4 g. Five adverse pregnancy outcomes (APOs) occurred (2 preterm births and 4 low birthweights); most of these cases had sustained elevation of CPK concentration and increased glucocorticoid dosages. No APOs occurred in the 2 patients who received continuous immunosuppressive medication. Continued use of pregnancy-compatible medications and control of disease activity with lower glucocorticoid dosages in pregnancies with PM/DM may be important to achieve good pregnancy outcomes.

Abstract 5462: Elevated creatine phosphokinase (CPK) as a strong predictor of aumolertinib (Au) treatment response in patients (pts) with advanced non-small cell lung cancer (NSCLC): post-hoc analysis of AENEAS

Abstract Background: In AENEAS trial (NCT03849768), first-line Au for EGFR-mutated, advanced NSCLC showed robust improvement in PFS over gefitinib (G). CPK elevation was the most common AE during Au treatment which may pose safety concerns. To evaluate the relationship between CPK elevation and Au efficacy, we performed a post-hoc analysis of AENEAS. Methods: AENEAS is a double-blind, randomized controlled phase III trial. Untreated advanced NSCLC pts with EGFR sensitizing mutations were assigned 1:1 to receive Au (110 mg QD) or G (250 mg QD). The primary endpoint was PFS. Secondary endpoints included ORR, DCR, DoR and DepOR. Data cutoff: Aug 1, 2021. Results: 37.9% (81/214) of pts receiving Au had CPK elevation, among whom the mPFS was 26.3 mos and was significantly longer (HR=0.45; 95% CI: 0.31-0.67; P&amp;lt;.0001) than that of the CPK-normal pts (133/214) at 13.9 mos. PFS benefits remained consistent across all prespecified subgroups. Also for all the secondary endpoints, CPK-elevated pts demonstrated significant benefits over CPK-normal pts (TABLE). Multivariable regression analysis revealed that CPK elevation was an independent predictor of prolonged PFS for pts receiving Au, with 54% reduced risk of progression or death for CPK-elevated pts compared with CPK-normal pts (HR=0.46; 95%CI: 0.31-0.68; P=.0001). Au demonstrated PFS benefits over G in both CPK-elevated pts (HR=0.40; 95% CI: 0.21-0.79; P=.0059) and CPK-normal pts (HR=0.63; 95% CI: 0.48-0.83; P=.0010), and the benefit was magnified in CPK-elevated pts. Further supported by post-hoc analysis of a phase 1/2 study (NCT02981108), PFS was also significantly prolonged in CPK-elevated pts receiving second or later line Au (17.7 vs 10.9 mos; HR=0.63; 95% CI: 0.46-0.87; P=.0049). Conclusion: Our study first revealed the predictive value of CPK elevation on improved treatment response of Au, which is of great significance to help guide medical care. Summary of Endpoints Elevated CPK(N=81) Normal CPK(N=133) PFS, months Median (95% CI) 26.3 (20.7-NA) 13.9 (12.4-19.8) HR (95% CI) 0.45 (0.31-0.67) P-value &amp;lt;0.0001 12-months PFS rate (95% CI) 84.9 (74.9-91.1) 59.4 (50.2-67.5) 24-months PFS rate (95% CI) 54.3 (42.4-64.7) 30.1 (21.9-38.8) DoR, months Median (95% CI) 23.5 (18.1-NA) 15.2 (10.2-19.2) HR (95% CI) 0.51 (0.33-0.79) P-value 0.0024 12-months DoR rate (95% CI) 77.7 (65.7-85.9) 55.8 (44.3-65.9) 24-months DoR rate (95% CI) 46.9 (33.7-59.0) 31.0 (20.9-41.6) ORR (95% CI), % 87.7 (78.5-93.9) 66.9 (58.2-74.8) OR (95% CI) 3.54 (1.64-7.64) P-value 0.0013 DCR (95% CI), % 98.8 (93.3-100.0) 89.5 (83.0-94.1) OR (95% CI) 9.59 (1.22-75.54) P-value 0.0318 DepOR, % Mean (Std) -50.5 (17.4) -42.0 (24.1) Range -100.0-3.6 -100.0-50.0 P-value 0.0105 Citation Format: Shun Lu, Chuan Li, Hong Jian, Xiaorong Dong, Jianhua Chen, Gongyan Chen, Yuping Sun, Yinghua Ji, Jiawei Wei, Si Sun, Zhenzhong Su, Qiu Sun, Hongying Wei, Qiong Wu. Elevated creatine phosphokinase (CPK) as a strong predictor of aumolertinib (Au) treatment response in patients (pts) with advanced non-small cell lung cancer (NSCLC): post-hoc analysis of AENEAS. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5462.

A Case of Childhood Onset of Extended Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis Phenotype with Pathogenic Polymerase Gamma Variation

Background: Ataxia neuropathy spectrum, including sensory ataxia neuropathy, dysarthria, and ophthalmoparesis (SANDO), is a part of polymerase gamma (POLG) gene-related disorder, a heterogeneous group of mitochondrial disorders. Childhood onset of the SANDO phenotype is rare, and we describe such a case here, probably the first from India. Clinical Description: A 17-year-old girl presented with progressive gait abnormality since 5 years of age, later associated with ptosis and seizures. On examination, she had atrophy of distal small muscles and absent tendon reflexes in addition to ataxia and ptosis. Differentials for a neurodegenerative disorder with cognitive sparing and ophthalmoplegia were suspected. Management: Investigations revealed a mild elevation in serum lactate, transaminases, and creatine phosphokinase, with abnormal neurophysiology showing primary muscle disease with symmetrical sensorimotor polyneuropathy, and a normal neuroimaging. Gene sequencing analysis for the mitochondrial disorder was done, which revealed a pathogenic variation in the POLG gene. The child was kept on supportive management, including antiepileptics. Conclusion: This case shows that the SANDO phenotype of POLG-related disorders, classically seen in adults, may rarely be seen in children. Our case highlights the fact that although many of the progressive neurodegenerative disorders have a nonspecific clinical presentation, biomarkers, and neurophysiologic abnormalities, a few important phenotypic clues and awareness of POLG-related disorders may enable a pediatrician to order focused genetic testing to delineate the etiology.

Jak inhibitors in vitiligo: a meta analysis.

Jak inhibitors in vitiligo: a meta analysis.

Perivascular fat attenuation index measured by coronary computed tomography angiography as a tool for assessment of ischaemia-causing lesions: a case report

BackgroundIt can be difficult to diagnose coronary artery disease in patients with acute coronary syndrome if coronary angiography does not identify stenosis. Coronary inflammation, which can contribute to the pathogenesis of coronary artery disease and acute coronary syndrome, can be quantified using the perivascular fat attenuation index. Furthermore, the perivascular fat attenuation index is a marker for all-cause mortality, cardiac-related mortality and impaired global coronary flow reserve.Case presentationHere we report a case of a patient presenting with symptoms of acute coronary syndrome. The patient had hypokinesis of the lateral-posterior wall of the left ventricle, decreased myocardial perfusion in the posterior wall myocardium and elevated myocardial troponin-T and creatine phosphokinase levels. However, coronary computed tomography angiography did not identify arterial stenosis. The patient did have an increased perivascular fat attenuation index, indicating coronary inflammation. Moreover, the fat attenuation index was higher around the left circumflex artery than around the right coronary artery or left anterior descending artery. Intravascular ultrasonography identified an intramural haematoma, leading to a diagnosis of type 3 spontaneous coronary artery dissection in the left circumflex artery.ConclusionsPerivascular fat attenuation index may be a useful tool to help identify and localise disease-causing lesions, and to direct further testing to confirm a diagnosis of spontaneous coronary artery dissection in acute coronary syndrome patients without significant arterial stenosis.

Efficacy and safety of baricitinib treatment for moderate to severe atopic dermatitis in real-world practice in Japan.

The authors evaluated the efficacy and safety of baricitinib, a Janus kinase 1/2 inhibitor, for atopic dermatitis (AD) in real-world practice. From August 2021 to September 2022, 36 patients aged ≥15 years with moderate to severe AD were treated with oral baricitinib 4mg/day plus topical corticosteroids. Baricitinib improved clinical indexes; the percent reduction at weeks 4 and 12 was a median of 69.19% and 69.98% for the Eczema Area and Severity Index (EASI), 84.52% and 76.33% for the Atopic Dermatitis Control Tool, and 76.39% and 64.58% for Peak Pruritus Numerical Rating Score, respectively. The achievement rate of EASI 75 was 38.89% and 33.33% at weeks 4 and 12, respectively. The percent reduction of EASI in the head and neck, upper limbs, lower limbs, and trunk was 56.9%, 68.3%, 80.7%, and 62.5% at week 12, respectively, with a significant difference between the head and neck versus the lower limbs. Baricitinib decreased thymus and activation-regulated chemokine, lactate dehydrogenase, and total eosinophil count at week 4. Baseline EASI of the head and neck negatively correlated with percent reduction of EASI at week 4, while baseline EASI of the lower limbs positively correlated with percent reduction of EASI at week 12. Treatment-emergent adverse events included elevation of creatine phosphokinase (11.1%), herpes labialis (5.6%), furuncle (8.3%), and exacerbation of AD (1%), without serious treatment-emergent adverse events. In this real-world study, baricitinib was well tolerated for patients with AD and achieved therapeutic effects comparable to those in clinical trials. High baseline EASI of the lower limbs might predict good treatment response at week 12, while high baseline EASI of the head and neck might predict poor treatment response at week 4 in baricitinib treatment for AD.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients

IntroductionThe pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. MethodsThe phase 2 trial enrolled Japanese pediatric patients (age 1–17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. ResultsFollowing administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. ConclusionsThe results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.

Dengue Fever Presenting with Severe Myositis-A Case Report

Dengue fever is one of the most common vector-borne diseases, which is a viral infection transmitted by female Aedes aegypti mosquitoes. It is most common in tropical countries like India. Dengue fever symptoms can range from a mild infection to severe flu-like sickness. Myalgia is a symptom of dengue infection. Dengue fever with myositis and/or high serum creatine phosphokinase (CPK) levels, on the other hand, is extremely uncommon. Dengue virus can cause myositis in many mechanisms. One of the most common mechanisms is by direct invasion of the myocytes by the dengue viruses. Myotoxins, Inflammatory cytokines have also been a part of the development of myositis. The clinical spectrum is broad, from the mild asymmetrical weakness of lower extremities to sudden progressive severe limb and trunk weakness, and even lung failure. This case study aims to show the rare neuromuscular complications of dengue fever, which can be managed well with a high index of suspicion. Our patient presented with fever and severe myalgia and was diagnosed with dengue. We started treating the patient with a provisional diagnosis of dengue-associated myositis. Significantly elevated CPK levels confirmed the myositis. Hereby, we are presenting a case of dengue fever with myositis with muscle weakness &amp; elevated creatine phosphokinase (CPK) levels who recovered completely with early suspicion of dengue-associated myositis and early management. Hence, Physicians should have a high index of suspicion and early management of dengue-associated neuromuscular complications.

Electroconvulsive Therapy for Neuroleptic Malignant Syndrome: A case report

IntroductionNeuroleptic malignant syndrome (NMS) is a rare syndrome observed in around 0.2% of psychiatric patients. This syndrome consists of the presentation of muscular rigidity, tachycardia, hyperpyrexia, leukocytosis and elevated levels of CPK. Any antipsychotic drug, including atypical ones, can cause this syndrome. This being an idiosyncratic response to dopamine receptor antagonist medications.The use of ECT in patients suffering from NMS is very effective, seeing the progressive resolution of the picture in the first sessions.ObjectivesThe patient was a 43-year-old man, whose somatic history only highlights hypothyroidism, and according to his psychiatric history, he was diagnosed of mental retardation and paranoid schizophrenia. He was a resident of a group home. And he was recently admitted to a mid-stay psychiatric unit. During this admission, the responsible doctor added haloperidol to his medication regimen. His other medications at the time were; valproic acid, risperidone and trazodone. A few days later, the patient began to present a dysthermic sensation (presenting a temperature of 39ºC) and drowsiness. A laboratory tests and a chest X-ray was performed, highlighting: leukocytosis and an increase in elevated creatine phosphokinase (CPK).Due to his recent exposure to 2 different antipsychotics, with fever, rigidity, and elevated CPK, we considered NMS. Antipsychotics were withdrawn and supportive measures were started. Within the next 2 days, his CPK level began to decline and the fever and leukocytosis resolved. But without resolving muscle rigidity. At the same time, he began to exhibit staring, negativism and prejudice delusions. Therefore, electroconvulsive therapy sessions were started.Methods.ResultsAfter the third session, his catatonic symptoms increased to better; he became more verbal, with less negativism and the psychotic symptomatology ceased. After the fifth session of ECT, he returned to his initial level and was able to walk to the bathroom without assistance and perform other activities of daily living.ConclusionsIt is extremely important that professionals specialized in psychiatry become familiar with ECT and consider this technique as treatment in cases of neuroleptic malignant syndrome.Disclosure of InterestNone Declared

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. Clinical data were collected from 58 patients with methicillin-resistant Staphylococcusaureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45g/L and standard creatinine clearance of 100mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤30mL/min] and 6mg/kg for patients with mild to moderate renal function (CLcr>30 and ≤60mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

Itch and Janus Kinase Inhibitors

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.

Comparison of the efficacy and safety of standard- and high-dose daptomycin: A systematic review and meta-analysis.

Standard doses of daptomycin at 4 and 6mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4-6mg/kg) and high-dose (HD, >6mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76 and OR 0.50, 95% CI 0.30-0.82) and HD2 group (OR 0.38, 95% CI 0.21-0.69 and OR 0.30, 95% CI 0.15-0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

P518 Safety of upadacitinib in ulcerative colitis: Long-term data from the phase 3 open-label extension study (U-ACTIVATE)

Abstract Background Upadacitinib (UPA), an oral reversible and selective JAK inhibitor, has demonstrated efficacy, with a well-characterised safety profile, in two replicate induction studies of UPA 45 mg once daily (QD; U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study of UPA 15 mg or UPA 30 mg QD (U-ACHIEVE maintenance).1 Here, we report safety data from the ongoing, Phase 3, open-label, 288-week long-term extension (LTE) study in patients with ulcerative colitis (UC) who previously participated in the induction studies. Methods Rates of treatment-emergent adverse events (TEAEs) and TEAEs of special interest were calculated by treatment sequence in patients who received ≥1 dose of UPA in the induction studies, maintenance study, or by the data cut-off of 13 December 2021 in the LTE study. Rates are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]), except for events that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs). PYs were calculated from the first dose of UPA 45 mg received during induction through to the last UPA dose received or the data cut-off date for ongoing patients. Results Overall, 1,308 patients representing 2,350.2 PYs of UPA exposure were evaluated (mean age: 43 years; female: 38%). Across treatment groups, EAERs of serious TEAEs, severe TEAEs, TEAEs leading to UPA discontinuation, TEAEs with reasonable possibility of being related to UPA, or TEAEs leading to death were numerically similar across all UPA treatment sequences (Table 1). EAERs of serious infections, herpes zoster, neutropenia, hepatic disorder, and creatine phosphokinase elevation were numerically higher with UPA 15 mg and 30 mg vs placebo; and creatine phosphokinase elevation with UPA 30 mg vs UPA 15 mg (Table 2). The EAER of anaemia was numerically lower with UPA 30 mg vs UPA 15 mg and placebo. Of note, no remarkable differences were observed in EAIRs of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, or malignancy (excluding non-melanoma skin cancer). Conclusion: Long-term use of UPA 15 or 30 mg among patients with UC continuing to benefit from prolonged therapy representing 2,350.2 PYs of exposure was well tolerated. The ongoing safety profile of UPA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses following 52 weeks’ maintenance therapy,1,2 or other immune-mediated indications for which UPA is approved.3,4

P179 Comparative benefit-risk profile of induction and maintenance therapy with upadacitinib versus placebo in patients with moderately to severely active ulcerative colitis

Abstract Background Upadacitinib (UPA) demonstrated efficacy and safety as induction and maintenance therapy for ulcerative colitis (UC) in Phase 3 trials U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026). This post-hoc analysis aims to characterise the benefit-risk profile of UPA induction and maintenance therapy vs placebo (PBO) in patients (pts) with moderately to severely active UC based on a number needed to treat/harm (NNT/NNH) analysis. Methods Efficacy and safety data from the pooled intention-to-treat population of U-ACHIEVE and U-ACCOMPLISH trials were included. Pts received UPA 45 mg (UPA45) once daily (QD) or PBO for 8 weeks (induction trials). Clinical responders (per Adapted Mayo score) at Week 8 of induction were re-randomised to receive UPA 15 mg (UPA15) or 30 mg (UPA30) QD, or PBO in the 52-week maintenance study. The primary efficacy endpoint was clinical remission per Adapted Mayo score. Secondary outcomes are listed in Table 1 and safety outcomes are listed in Table 2. N, percentages, and outcome differences compared by Z test were reported. NNT/NNH was calculated as the inverse of the difference in proportions achieving efficacy/safety outcomes for UPA vs PBO. Positive NNT values indicate greater efficacy and negative NNH values imply lower safety risk for UPA vs PBO. Results A significantly greater proportion of pts achieved clinical remission at induction (UPA45 29.9% vs PBO 4.4%) and maintenance (UPA15 40.4%, UPA30 53.6% vs PBO 10.8%) with UPA vs PBO, as well as all secondary endpoints (all p&amp;lt;0.001; Table 1). The NNT for clinical remission at Week 8 was 4.0, ranging from 2.1 to 9.6 for secondary endpoints. At Week 52, the NNT for clinical remission was 2.4; NNTs for secondary endpoints ranged from 1.8 to 5.9 (Table 1). At Week 8, adverse events (AEs) were lower for worsening of UC for UPA45 vs PBO-treated pts and greater for creatine phosphokinase (CPK) elevation, acne, neutropenia, and lymphopenia (p≤0.01). At Week 52, AEs were lower for UPA15 and UPA30 vs PBO for worsening of UC, AEs leading to discontinuation (UPA15 only), and arthralgia (UPA30 only), and greater for CPK elevation, herpes zoster, hepatic disorder (UPA15 only), and neutropenia (UPA30 only) (p≤0.05; Table 2). All other AEs were similar between UPA and PBO. Among the safety outcomes significantly different between UPA and PBO, the NNH for UPA vs PBO ranged from –16.1 to 25.6 (Table 2). Conclusion This post-hoc Phase 3 analysis demonstrates greater efficacy and generally comparable safety of UPA vs PBO, indicating a favourable benefit-risk profile for UPA in pts with moderately to severely active UC.

Safety of upadacitinib in Latin American patients with rheumatoid arthritis: an integrated safety analysis of the SELECT phase 3 clinical program

Introduction/objectivesRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by ongoing inflammation and degradation of synovial joints. The oral JAK inhibitor, upadacitinib, is approved for RA. We conducted an integrated safety analysis of upadacitinib 15 mg once daily (QD) in patients from Latin America (LATAM) versus the rest of the world (RoW).MethodsTreatment-emergent adverse events (AEs) and laboratory data from six phase 3, randomized controlled trials, adjusted for upadacitinib 15 mg QD use in RA, were analyzed.ResultsOverall, 3209 patients received upadacitinib 15 mg QD for 7024 patient-years (PY). LATAM patients (n = 725) had a mean upadacitinib exposure of 1518 PY. Baseline characteristics were generally similar between LATAM and RoW populations. AE rates (including serious/opportunistic infections, tuberculosis, and herpes zoster) and deaths were comparable between populations. LATAM patients had lower serious AE rates per 100 PY (9.4 vs 14.0 E/100 PY) and discontinuation-related AEs (3.9 vs 6.0 E/100 PY) versus RoW. Rates of cardiovascular events were low (≤ 0.5 E/100 PY) and similar between populations. Malignancies, excluding non-melanoma skin cancer, were less common in the LATAM population versus RoW (0.2 vs 1.0 E/100 PY). Laboratory abnormalities were similar between populations, with decreases in hemoglobin, lymphocyte, and neutrophil counts, and elevations in liver enzymes and creatine phosphokinase. Mean change from baseline in low- and high-density lipoprotein cholesterol was generally comparable between LATAM and RoW populations.ConclusionUpadacitinib 15 mg QD demonstrated a consistent safety profile across LATAM and RoW patient populations, with no new safety risks observed.Trial registration numbersSELECT-EARLY, NCT02706873; SELECT-NEXT, NCT02675426; SELECT-COMPARE, NCT02629159; SELECT-MONOTHERAPY, NCT02706951; SELECT-BEYOND, NCT02706847; SELECT-CHOICE, NCT03086343.Key Points• This study assessed the safety of upadacitinib 15 mg in patients with rheumatoid arthritis from Latin America compared with patients from the rest of the world participating in the SELECT phase 3 program.• Safety was generally similar between the two groups, including serious and opportunistic infections, tuberculosis, herpes zoster, and cardiovascular events. Malignancy, major adverse cardiovascular events, and venous thromboembolic events were infrequent in the Latin American patients.• Consistent with the known safety profile of upadacitinib, serious infections, herpes zoster, and laboratory abnormalities were the most common safety events in the Latin American population.

Creatine phosphokinase enzyme elevation in two third-level hospitals of Córdoba

HyperCKemia is defined as the elevation of creatine phosphokinase (CK) levels greater than 1.5 times the upper limit (CK>285 U/L), being produced by multiple causes, which vary according different populations. The main objective of the study was to know the frequency of hyperCKemia in two hospitals in Córdoba and its main causes. Retrospective analytical study in two hospitals in Córdoba, Argentina, where all patients over 18 years of age who presented CK values ​​greater than 285 U/L on at least 2 occasions in a period between 1 and 4 weeks were identified, between the years 2015 and 2017. 254 patients with hyperCKemia were identified, the majority were male (n=181, 71.3%) and their median age was 65 years (interquartile range 25-75%=50-73 years). The main causes of hyperCKemia were ischemic myopathy in 99 (39%) patients and drug-induced myopathies in 45 (17.7%), with statins being the most frequently involved drugs in 31 cases. In only 3.1% of the cases the final diagnosis was not reached. Drug-induced hyperCKemias, when compared to other causes, occurred more frequently in patients with a history of chronic kidney disease (9/45 [20%] vs 18/209 [8.6%], p = 0.025) and in non-smokers (41/45 [91.1%] vs. 157/209 [75.1%], p=0.019). 254 cases of hyperCKemia were observed, the main causes being of ischemic origin and secondary to drug use, especially statins.

357: MORE THAN MYALGIA: STATIN-INDUCED IMMUNE-MEDIATED NECROTIZING MYOPATHY

Introduction: Statins rank amongst the top ten most prescribed medications in the United States for their cardiovascular benefits. Common toxic side effects include elevated liver enzymes and myalgia including rhabdomyolysis. We report a case of a previously healthy middle-aged female who recently started statin therapy and developed progressive muscle weakness requiring mechanical ventilation. Description: A 58-year-old female with recently diagnosed hyperlipidemia started on atorvastatin (40 mg) 2 months prior to presentation was admitted with 2 weeks of progressively worsening proximal muscle weakness and oropharyngeal dysphagia. Admission labs showed a significantly elevated creatine phosphokinase (CPK) (3,742 U/L) and aldolase level (41.1 U/L). She was empirically started on IVIG for presumed myasthenic crisis or possible inflammatory myositis. On day 2, she exhibited worsening proximal muscle weakness and an inability to lift her extremities against gravity. On physical exam, she had 1/5 strength of proximal muscle groups and 4/5 strength of distal muscle groups with an otherwise intact neuromuscular exam. On day 3, she had worsening dysphagia and aspiration pneumonitis requiring endotracheal intubation. An EMG showed myopathic features in the proximal musculature without any evidence of neuropathy. She was empirically started on steroids with some improvement. After 1 week, the anti-HmgCoA reductase antibody returned severely positive (>200). Given the high specificity of this test, her presentation was ultimately deemed consistent with statin induced immune-mediated necrotizing myopathy, and she was started on Cellcept (MMF) and high-dose steroids. Discussion: The case highlights the devastating consequences that can result from a very commonly prescribed medication class and the importance of actively evaluating for adverse medication effects. Statin therapies are guideline directed in patients with cardiovascular disease such as coronary artery disease and stroke. Myalgia without significant weakness are a common side effect and therapy includes discontinuing the offending agent. In the presence of severe weakness, statin induced immune-mediated necrotizing myopathy should be considered, as it could be detrimental and may require mechanical ventilation and treatment with immunosuppressants.

Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor–Induced Myocarditis

BackgroundMyocarditis is a dreaded and unpredictable complication of immune checkpoint inhibitors (ICI). We sought to determine whether routinely measured biomarkers could be helpful in monitoring for ICI myocarditis. ObjectivesThe authors examined biomarker trends of patients on ICI and their association with the incidence of ICI myocarditis and outcomes. MethodsWe conducted an observational cohort study of adults who received at least one dose of ICI at Michigan Medicine between June 2014 and December 2021 and underwent systematic serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy. ResultsAmong 2,606 patients (mean age 64 ± 13 years; 60.7% men), 27 (1.0%) were diagnosed with ICI myocarditis. At diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR: 1.83; 95% CI: 1.59-2.10) and all-cause mortality (HR: 1.10; 95% CI: 1.01-1.20) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis. ConclusionsICI myocarditis is associated with changes in AST, ALT, and CPK. An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis.