Elevated Creatine Phosphokinase Research Articles

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15mg once daily or adalimumab 40mg every other week were switched to the alternate therapy by week26. Efficacy was evaluated through 228weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week264. Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week26. Clinically relevant improvements in all efficacy measures were observed through 228weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. NCT02629159.

OP10 Efficacy and safety of upadacitinib in patients with moderately to severely active Crohn’s Disease: results from the U-ENDURE long-term extension

Abstract Background Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD).1 The U-ENDURE (NCT03345823) maintenance study and long-term extension (LTE) evaluate the long-term efficacy and safety of UPA maintenance therapy. Here, we report the results of the U-ENDURE LTE. Methods Patients (pts) completing the U-ENDURE 52-week (wk) maintenance study were eligible to participate in the LTE and continue their previously assigned treatment (placebo [PBO], UPA 15 mg [UPA15] once daily [QD], or UPA 30 mg [UPA30] QD; blinded until the last pt completed maintenance wk52). Clinical response, clinical remission, endoscopic response, endoscopic remission, as well as high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated as-observed up to wk48 of the LTE among pts (PBO [N = 89], UPA15 [N = 107], UPA30 [N = 173]); excluding pts who received open-label UPA30 rescue therapy. Safety was assessed in all pts (PBO [N = 223], UPA15 [N = 221], UPA30 [N = 229]) from wk0 of the maintenance study up to LTE wk204 (cut-off date: 01 Aug 2023). Results At LTE wk0, the SF/APS clinical remission rates were 73.0%, 78.3%, and 80.3% for PBO, UPA15, and UPA30, respectively (Figure 1A). Similar rates were reported at LTE wk0 for CDAI clinical remission (PBO 75.3%, UPA15 81.3%, UPA30 80.9%; Figure 1B) and clinical response (CR-100: PBO 79.5%, UPA15 84.9%, UPA30 84.4%). Rates of clinical remission were stable through wk48 of the LTE. Endoscopic response (PBO 32.9%, UPA15 59.6%, UPA30 66.5%) and remission rates (PBO 27.8%, UPA15 42.4%, UPA30 47.3%) at LTE wk0 were sustained through wk48 with UPA while decreased with PBO (Figure 1C-D). At LTE wk0, the mean [95% CI] change from induction BL in hs-CRP was 1.8 [–0.4, 4.1], –13.2 [–17.9, –8.6], and –12.8 [–16.8, –8.9] for PBO, UPA15, and UPA30, respectively; sustained through wk48. Similar results were observed with FCP (mean [95% CI] change from induction BL: PBO 126 [–103, 356], UPA15 –2946 [–4121, –1772], UPA30 –1871 [–2577, –1165]). Severe adverse events (AEs) and serious AEs were lower with UPA treatment compared with PBO (Table 1). The rates of most AEs of special interest were similar between UPA and PBO; however, numerically higher rates of herpes zoster, adjudicated gastrointestinal perforations, neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders were reported in pts treated with UPA vs PBO (Table 1). Conclusion In pts completing wk48 of the LTE, sustained efficacy was observed in clinical and endoscopic endpoints with over 2 years of UPA treatment, while maintaining an overall positive safety profile in pts with CD. Reference: 1. Loftus EV Jr, et al. N Engl J Med. 2023;388:1966–80

Clinical predictors of left ventricular thrombus after myocardial infarction as detected by magnetic resonance imaging.

The diagnosis of a left ventricular (LV) thrombus in patients with ST-segment elevation myocardial infarction (STEMI) remains challenging. The aim of the current study is to characterize clinical predictors for LV thrombus formation, as detected by cardiac magnetic resonance imaging (CMRI). We retrospectively evaluated 337 consecutive STEMI patients. All patients underwent transthoracic echocardiography (TTE) and CMRI during their index hospitalization. We developed a novel risk stratification model (ThrombScore) to identify patients at risk of developing an LV thrombus. CMRI revealed the presence of LV thrombus in 34 patients (10%), of whom 33 (97%) had experienced an anterior wall myocardial infarction (MI), and the majority (77%) had at least mildly reduced left ventricular ejection fraction (LVEF < 45%). The 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 levels, lack of ST-segment elevation (STe) resolution, elevated creatine phosphokinase levels, and STe in anterior ECG leads are robust independent predictors for developing an LV thrombus. These variables were incorporated to construct the ThrombScore: a simple six-point risk model. The odds ratio for developing thrombus per one-point increase in the score was 3.2 (95% CI 2.1-5.01; p < 0.001). The discrimination analysis of the model revealed a c-statistic of 0.86 for thrombus development. The model identified three distinct categories (I, II, and III) with corresponding thrombus incidences of 0%, 1.6%, and 27.6%, respectively. ThrombScore is a simple and practical clinical model for risk stratification of thrombus formation in patients with STEMI.

Carbon Monoxide Alleviates Post-ischemia-reperfusion Skeletal Muscle Injury and Systemic Inflammation.

Restoration of blood flow in skeletal muscle after a prolonged period of ischemia induces muscular ischemia-reperfusion injury, leading to local injury/dysfunction in muscles followed by systemic inflammatory responses. However, preventive/curative agents for skeletal muscle ischemia injury are unavailable in clinics to date. Increasing evidence has validated that carbon monoxide (CO) prevents the progression of ischemia-reperfusion injury in various organs owing to its versatile bioactivity. Previously, we developed a bioinspired CO donor, CO-bound red blood cells (CO-RBC), which mimics the dynamics of RBC-associated CO in the body. In the present study, we have tested the therapeutic potential of CO-RBC in muscular injury/dysfunction and secondary systemic inflammation induced by skeletal muscle ischemia-reperfusion. The results indicate that CO-RBC rather than RBC alone suppressed elevation of plasma creatine phosphokinase, a marker of muscular injury, in rats subjected to both hind limbs ischemia-reperfusion. In addition, the results of the treadmill walking test revealed a significantly decreased muscular motor function in RBC-treated rats subjected to both hind limbs ischemia-reperfusion than that in healthy rats, however, CO-RBC treatment facilitated sustained muscular motor functions after hind limbs ischemia-reperfusion. Furthermore, CO-RBC rather than RBC suppressed the production of tumour necrosis factor (TNF)-α and interleukin (IL)-6, which were upregulated by muscular ischemia-reperfusion. Interestingly, CO-RBC treatment induced higher levels of IL-10 compared to saline or RBC treatments. Based on these findings, we suggest that CO-RBC exhibits a suppressive effect against skeletal muscle injury/dysfunction and systemic inflammatory responses after skeletal muscle ischemia-reperfusion.

Transdermal exposure to Chrome-III oxide resulting in intoxicaitons and morbidity in two tanning workers—a case report

Here, we report two cases of chrome-III oxide intoxications following transdermal exposure in tanning workers. A 58-year-old man (case 1) and his 41-year-old co-worker (case 2) were brought to our ED with unconsciousness six hours after accidental transdermal exposure to chrome-III oxide crystals (Tankrom® AB, Chrome-III oxide 25.5% and Schorlemmer Basicity 33%). Upon arrival, both patients presented with agitation and chemical burns affecting 11% (case 1) and 3% (case 2) of their total body surface area, respectively. Chemical burns were mainly distributed on injured skin. Initial arterial blood gas analysis revealed moderate (case 1, pH: 7.268) to mild acidosis (case 2, pH: 7.352). One of our patients (case 1) had significant respiratory depression. Laboratory results of case 1 and case 2 showed increased white blood cell counts, (16,630 mm3 and 19,950 mm3) and elevated blood glucose (178 mg/dL and 193 mg/dL), creatinine (1.33 mg/dL and 1.52 mg/dL), liver enzyme (aspartate aminotransferase/alanine aminotransferase of 416/322 U/L and 141/118 U/L) and creatine phosphokinase level (474 U/L and 566 U/L), respectively. Radiologic examinations revealed an orbital wall fracture and L2 compression fracture in case 1, while case 2 had a subdural hematoma, subarachnoid hemorrhage and scapular fracture and had to undergo an operation for external ventricular drainage. Both patients became alert on day three (case 1) and day six (case 2) and were discharged on day 27. We serially measured their serum and urinary chromium concentrations after hospital arrival. The calculated serum half-lives were 35.7 hours and 25.1 hours, and urinary half-lives were 2.3 hours and 2.5 hours in case 1 and case 2, respectively. We suggest that transdermal exposure to chrome-III oxide, especially to injured skin, may result in significant toxicity and morbidity. Therefore, it is essential to take necessary precautions and preventive measures to avoid transdermal exposure to chromium.

Statin-Induced Rhabdomyolysis: A Rare Case

ABSTRACT Statins are a group of lipid-lowering agents currently used as mainstay agents in the primary and secondary prevention of atherosclerotic cardiovascular heart disease. Rhabdomyolysis is one of the rare adverse effects of statin therapy, the incidence of which increases in the presence of risk factors. We report a rare case of statin-induced rhabdomyolysis presenting with acute kidney injury (AKI) requiring dialysis in the absence of risk factors. A 58-year-old diabetic and hypertensive female presented with pain and weakness of lower limbs, difficulty in walking, shortness of breath, and decreased urine output. She was receiving statin therapy for the past 1 week. Her blood investigations showed elevated creatine phosphokinase (CPK) and renal parameters. Electromyography and magnetic resonance imaging of thigh and calf muscles were suggestive of myositis. Statin was withdrawn and hemodialysis was done. The patient recovered gradually with no residual deficit. Statin-induced rhabdomyolysis is a rare but serious adverse effect requiring timely management. CPK levels along with thorough history and physical examination are useful to establish the diagnosis. Treatment is hydration and supportive therapy when diagnosed early. Hemodialysis is required in severe cases with AKI.

Role of Ayurveda in the Management of Becker Muscular Dystrophy: A Case Study

Abstract Muscular dystrophies are a group of genetic disorders that lead to a gradual weakening of muscles, resulting in increased disability over time. Becker muscular dystrophy (BMD) is one such condition and is inherited through an X-linked recessive pattern, primarily affecting males. Symptoms of BMD typically begin in the teenage years or late twenties. Initial signs may include muscle cramps during exercise and reduced stamina. Over time, there is a gradual loss of muscle bulk in the hips, pelvis, thighs, and shoulders, often leading to a tendency to walk on toes. In Ayurveda, the factors contributing to this disease are believed to be an aggravation of Vata (one of the three doshas), depletion of Mamsa (muscle tissue), and Meda (fat tissue), impaired digestive fire, and blockage of functional channels (Srotorodha). The present case involved a 15-year-old male with weakness in both lower limbs for 4 years, a decrease in muscle mass around the pelvic and thigh area for 3 years, and an increase in calf muscle size for 3 years. The patient exhibited pseudohypertrophy in both calf muscles and positive Gower’s sign, along with a positive family history and elevated creatine phosphokinase levels, leading to a diagnosis of BMD. The treatment approach incorporated Panchakarma therapies and internal Ayurvedic formulations in line with the management of Sarvang Vata disorder. The treatment was administered in four sessions, with a 3-month gap between each therapy session. After a year of treatment, there was not only a halt in the progression of the disease but also a notable improvement in lower limb strength, which increased from 4 to 4+. In addition, there was an increase in proximal muscle mass, from 12.5 inches to 13 inches, and a reduction in calf muscle size and tightness. This promising outcome suggests the potential for managing the disease using Ayurvedic principles and therapies.

Therapeutic insights: Use of ceftazidime-avibactam in pediatric patients.

The increasing worldwide prevalence of multidrug-resistant (MDR) bacteria underscores the pressing demand for innovative therapeutic solutions. Ceftazidime-avibactam (CAZ-AVI) represents a promising new drug combination that has received approval for specific infection types. However, there is limited information regarding its application in pediatric patients. This study investigates the effectiveness and adverse reactions associated with CAZ-AVI treatment in pediatric patients with life-threatening infections caused by MDR pathogens. The study was conducted at a tertiary children's hospital between December, 2021 and July, 2023. A total of 21 patients with life-threatening infections caused by MDR pathogens were enrolled in the study. All patients had underlying medical conditions: 10 had cerebral palsy, four had congenital neurometabolic disease, two had Nieman-Pick disease, two had cystic fibrosis, two had primary immunodeficiency, and one had leukemia. Among these, 12 patients had tracheostomies. Eight patients received CAZ- AVI monotherapy, and 13 patients received combination therapy. Microbiological eradication was achieved in 18 patients (85.7%), and a clinical response was observed in 20 patients (95.2%). Two patients (9.5%) experienced relapse with the same bacteria. One patient developed anaphylaxis, and one patient had elevated creatine phosphokinase levels that normalized following discontinuation of treatment. One patient died during the study period due to gastrointestinal bleeding. Ceftazidime-avibactam may be a promising new drug option for the treatment of life-threatening infections caused by MDR Gram-negative microorganisms in pediatric patients. However, further studies with larger case series are needed to further evaluate the efficacy and safety of CAZ-AVI in this population.

A Rare Clinical Scenario of Hypothyroid-induced Rhabdomyolysis

Abstract Muscle involvement is common in hypothyroidism and is seen in nearly 80% of the cases. However, rhabdomyolysis is a rare manifestation and is usually triggered by precipitating factors such as exercise, statins, and toxins. We describe the case of a 58-year-old woman with de novo hypothyroidism presenting with severe rhabdomyolysis requiring hemodialysis. A 58-year-old diabetic and hypertensive female was presented at our tertiary care center with symptoms of generalized weakness, difficulty in walking, and decreased urine output. Her blood investigations showed elevated creatine phosphokinase (CPK), renal parameters, and thyroid-stimulating hormone (TSH) levels suggestive of autoimmune thyroiditis with rhabdomyolysis. She was treated with thyroid hormone supplementation and hemodialysis. The patient recovered gradually with normalization of renal parameters. Although muscle involvement is common in hypothyroidism, rhabdomyolysis is a rare manifestation. Diagnosis is established by demonstrating elevated CPK and TSH levels. Management consists of hydration and thyroid hormone supplementation. Hemodialysis is required in severe cases with established acute kidney injury.

Update of Olverembatinib (HQP1351) Overcoming Ponatinib and/or Asciminib Resistance in Patients (Pts) with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL)

Background Olverembatinib, a novel, potent BCR::ABL1 tyrosine kinase inhibitor (TKI), shows strong antitumor activity in pts with CML and Ph + ALL. Here, we report on the safety, efficacy, and pharmacokinetic (PK) profiles of olverembatinib in pts with CML (all phases) and Ph + ALL outside of China, particularly in pts previously treated with ponatinib and/or asciminib. Methods Olverembatinib was administered orally once every other day (QOD) in continuous 28-day cycles. In the monotherapy cohort, pts were enrolled after treatment failure on at least 2 prior TKIs and randomized to olverembatinib QOD 30, 40, or 50 mg. In the combination cohort, pts with Ph + B-cell precursor (BCP) ALL or lymphoid CML-BP (CML-LBP) resistant to at least 1 TKI were enrolled and received olverembatinib (30 or 40 mg) QOD in combination with blinatumomab. Results As of June 30, 2023, 76 pts were enrolled, including 57 with CML-CP and 19 with advanced Ph + leukemia. The median (range) age was 54.5 (21-80) years, and 56.6% of pts were male. In all, 11 (14.5%), 23 (30.3%), and 39 (51.3%) pts had received 2, 3, and ≥ 4 prior TKIs, respectively. A total of 52.6% of pts were previously treated with ponatinib, of whom 67.5% were resistant and 25.0% intolerant to the drug, and 7.5% experienced treatment failure for other reasons. A total of 27.6% of pts were previously treated with asciminib, of whom 71.4% were resistant and 19.1% intolerant to the agent, and 9.5% experienced treatment failure for other reasons. At baseline, 32% of pts had T315I mutations, 38% hypertension, and 17.1% other cardiovascular comorbidities. Median (range) treatment duration was 24.1 (0-134) weeks, and PK profiles were similar to historical PK data on Chinese pts. Twelve pts with CML-CP and 7 with advanced Ph + leukemia discontinued treatment: 4 because of AEs, 7 disease progression, and 8 other reasons. A total of 54 of 65 (83.1%) pts who received ≥ 1 dose of olverembatinib experienced any-grade TRAEs. Grade ≥ 3 AEs occurring in ≥ 3 pts (≥ 4.6% incidence) included thrombocytopenia (17%); neutropenia (13.8%); elevated blood creatine phosphokinase (13.8%); leukopenia (7.7%); and anemia and elevated lipase (4.6% each). Ten (15.4%) pts experienced olverembatinib treatment-related serious AEs, of which each were experienced by 1 (1.5%) pt. Two (3.1%) pts discontinued the study because of TRAEs. No TRAE-associated deaths were reported. Olverembatinib showed sustained antileukemic activity in pts with CML and Ph + ALL (Table 1). Among 50 efficacy-evaluable pts with CML-CP, the rate of complete cytogenetic response (CCyR) was 57% (25/44) and major molecular response (MMR) 43% (21/49). Efficacy improved over time; the MMR rate in pts with CML-CP treated for 6 months was 66% and 88% in pts treated for 12 months. Among pts whose disease failed ≥ 4 prior TKIs, CCyR and MMR rates were 57% (13/23) and 42% (11/26), respectively. In pts with CML-CP harboring the T315I mutation, rates of CCyR and MMR were 60% (9/15) and 44% (7/16), respectively, and 55% (16/29) and 42% (14/33) in pts without the T315I mutation. Among evaluable ponatinib-failed pts, 8/15 (53%) achieved CCyR and 6/16 (38%) MMR. Among pts who failed asciminib therapy, 3/7 (43%) achieved CCyR and 3/8 (38%) MMR. Of 8 pts with CML-CP who had prior exposure to both ponatinib and asciminib, 2 (25%) achieved MMR. At 24 months, PFS was 75% (95% CI, 56.1-86.7) and OS was 97.6% (95% CI, 90.8-99.4). Thirteen pts with advanced Ph + leukemia were efficacy-evaluable, of whom 3 (23%) achieved MMR; only 1 of 3 pts with the T315I mutation achieved MMR; the other 2 were also resistant to ponatinib treatment. The median (95% CI) PFS of efficacy-evaluable pts with advanced leukemia was 12.7 (4-19.5) months. In the combination cohort, 2 pts with Ph + BCP ALL received olverembatinib 30 mg QOD with blinatumomab; both achieved CCyR and 1 achieved a negative MRD status after 1 treatment cycle. Conclusions Olverembatinib alone or combined with blinatumomab was efficacious and well tolerated in pts with heavily pretreated CML or Ph + ALL . Olverembatinib monotherapy was potent in pts who were either resistant or intolerant to ponatinib and/or asciminib, regardless of T315I mutation status. Olverembatinib may provide an effective new treatment option for pts after failure of 2 or more TKIs. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022.

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m−2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485.

Deucravacitinib, an Oral, Selective, Allosteric Tyrosine Kinase 2 Inhibitor, in Moderate to Severe Plaque Psoriasis: Evaluation of Creatine Phosphokinase Elevations in the Phase 3 POETYK PSO-1 and PSO-2 Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in the US, EU, and other countries for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. In the phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) trials, deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated. This pooled safety analysis of POETYK PSO-1 and PSO-2 assessed changes from baseline in creatine phosphokinase (CPK) levels and CPK elevations and rhabdomyolysis adverse events (AEs) in patients receiving placebo, deucravacitinib, or apremilast.&#x0D; Methods: Patients with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Shifts from baseline in severity grade (Common Terminology Criteria for Adverse Events [CTCAE] version 5) of CPK levels were analyzed. Elevated CPK and rhabdomyolysis adverse events (AEs) were reported.&#x0D; Results: The pooled population included 1683 patients (placebo, n=419; deucravacitinib, n=842; apremilast, n=422). At baseline, the proportions of patients with grade ≥1 CPK levels were comparable (placebo, 6.3%; deucravacitinib, 5.9%; apremilast, 7.4%). During Weeks 0-16, worsening of CPK levels by &gt;1 CTCAE grade from baseline occurred at similar rates in patients receiving placebo (2.2%), deucravacitinib (2.5%), and apremilast (1.4%). Most deucravacitinib-treated patients maintained their baseline CPK CTCAE grade or shifted to a lower grade through Week 52. Elevated CPK AEs were reported in 1.2% (placebo), 2.7% (deucravacitinib), and 0.7% (apremilast) of patients through Week 16. Exposure-adjusted incidence rates (EAIRs) of elevated CPK AEs through Week 52 were comparable across treatments (placebo, 4.5/100 person-years [PY]; deucravacitinib, 4.7/100 PY; apremilast, 3.6/100 PY). Two deucravacitinib-treated patients (0.2/100 PY) and 1 apremilast-treated patient (0.4/100 PY) discontinued due to AEs of asymptomatic elevated CPK. Two deucravacitinib-treated patients had rhabdomyolysis with potential inciting events, one of which was associated with CPK elevation.&#x0D; Conclusion: Most deucravacitinib-treated patients maintained their baseline CPK grade or shifted to a lower grade through Weeks 16 and 52. The EAIR of CPK elevation AEs were comparable across treatment groups over 52 weeks.

Abstract 17245: Statin Induced Necrotizing Autoimmune Myositis

Description of Case: A 64 year old female with hypertension, hyperlipidemia, and type 2 diabetes presented to the emergency room for 3-4 months of progressively worsening bilateral lower extremity weakness with associated edema, but without any reports of pain. The patient had significant impairments in her daily function and now required a cane to ambulate. The patient was found to have significantly impaired strength in the bilateral lower extremities with particular involvement of the proximal thigh muscles. The patient was noted to have a markedly elevated creatine phosphokinase (CPK) to 16,000 and a moderate transaminitis. The patient underwent evaluation with an MRI which revealed several areas of bilateral necrotizing myositis. The patient’s autoimmune markers were remarkable for a positive HMG-CoA reductase antibody and a diagnosis of statin induced necrotizing autoimmune myositis was made. The patient was started on pulse dose steroids without much improvement in her weakness and functional ability. The patient was therefore started on intravenous immunoglobulin with a rapid improvement in her symptoms. The patient was discharged on long term glucocorticoid therapy with appropriate prophylactic medications. Discussion: Statin induced necrotizing autoimmune myositis (SINAM) is a very rare form of autoimmune myopathy that is characterized by rapidly progressive proximal muscle weakness along with other potential extramuscular manifestations in the setting of statin use. SINAM should be suspected in any patient on a statin, regardless of duration of treatment, who presents with proximal muscle weakness and a markedly elevated CPK, often &gt; 1000. Treatment, like other forms of autoimmune myopathies, is often centered around immunomodulatory therapies such as high dose glucocorticoids, intravenous immunoglobulin, and long term immunosuppressants. Despite rapid initiation of aggressive treatment, severe forms of the disease have a high mortality as there may be involvement of the respiratory musculature leading to respiratory failure. Given the rarity of this condition, along with the variability in presentation related to the onset of statin therapy, diagnosis and treatment of this entity remains poorly understood.

Higher Prevalence of Nonsense Pathogenic DMD Variants in a Single-Center Cohort from Brazil: A Genetic Profile Study That May Guide the Choice of Disease-Modifying Treatments.

Dystrophinopathies are muscle diseases caused by pathogenic variants in DMD, the largest gene described in humans, representing a spectrum of diseases ranging from asymptomatic creatine phosphokinase elevation to severe Duchenne muscular dystrophy (DMD). Several therapeutic strategies are currently in use or under development, each targeting different pathogenic variants. However, little is known about the genetic profiles of northeast Brazilian patients with dystrophinopathies. We describe the spectrum of pathogenic DMD variants in a single center in northeast Brazil. This is an observational, cross-sectional study carried out through molecular-genetic analysis of male patients diagnosed with dystrophinopathies using Multiplex Ligation-dependent Probe Amplification (MLPA) followed by Next-Generation Sequencing (NGS)-based strategies. A total of 94 male patients were evaluated. Deletions (43.6%) and duplications (10.6%) were the most recurring patterns of pathogenic variants. However, small variants were present in 47.1% of patients, most of them nonsense variants (27.6%). This is the largest South American single-center case series of dystrophinopathies to date. We found a higher frequency of treatment-amenable nonsense single-nucleotide variants than most previous studies. These findings may have implications for diagnostic strategies in less-known populations, as a higher frequency of nonsense variants may mean a higher possibility of treating patients with disease-modifying drugs.

Rhabdomyolysis associated with newer-generation anti-seizure medications (ASMs): a real-world retrospective and pharmacovigilance study.

Objective: Rhabdomyolysis is a potentially fatal adverse reaction mostly triggered by certain medications. Few real-world studies have shown a clear association between newer-generation anti-seizure medications (ASMs) and rhabdomyolysis. We sought to quantify the risk and evaluate the clinical features and management of rhabdomyolysis associated with newer-generation ASMs. Methods: Data were retrieved from the US FDA Adverse Event Reporting System database (FAERS) from 2018 to 2022 on newer-generation ASMs to identify rhabdomyolysis events, and disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports from 2012 to 31 December 2022 on newer-generation ASMs-induced rhabdomyolysis were retrieved for retrospective analysis. Results: A total of 1,130 rhabdomyolysis reports from the FAERS database were considered. Levetiracetam had the greatest proportion and the highest positive signal values of rhabdomyolysis. The RORs (95% CIs) for newer-generation ASMs were, in descending order, levetiracetam 8.01 (7.26-8.84), lamotrigine 3.78 (3.25-4.40), oxcarbazepine 3.47 (2.53-4.75), pregabalin 2.75 (2.43-3.12), lacosamide 1.85 (1.29-2.65), topiramate 1.64 (1.25-2.15), and gabapentin 1.32 (1.13-1.55). Twenty-six case reports showed evidence of rhabdomyolysis, and levetiracetam (65.4%) was the most frequently reported agent. The median age was 32years; typical initial symptoms included muscle weakness (34.8%), myalgia (34.8%), backache (17.4%), fatigue (13.0%) and leg pain (8.7%). The median time to onset of rhabdomyolysis was 2days. All cases had elevated creatine phosphokinase (CPK), and some cases were accompanied by elevated creatinine (57.1%) and myoglobinuria (53.8%). Cessation of ASMs could lead to complete clinical remission. The median time for creatine phosphokinase (CPK) normalization was 8days. Conclusion: This study identified 7 newer-generation ASMs with significant rhabdomyolysis reporting associations. Prescribers should be more aware of this risk and teach patients to recognize rhabdomyolysis signs/symptoms early.

A Case of Anti-3-hydroxy-3-methylglutaryl-coenzyme A Reductase Myopathy Associated With Advanced Cervical Carcinoma.

Necrotizing autoimmune myopathy is characterized by skeletal muscle weakness and is frequently associated with cancer. Absence of treatment can lead to severe muscular atrophy but initial symptoms may be insidious and delay the diagnosis. Here, we describe the case of a 70-year-old woman who was diagnosed with mnti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy during chemotherapy course for cervical cancer. A 70-year-old woman received chemotherapy for an advanced cervical carcinoma. She had no other relevant medical history and did not take statins. During the treatment she presented muscle weakness and myalgia. Biological tests showed elevated creatine phosphokinase level (3750 IU/l) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies were detected in the serum. The electroneuromyogram showed short myotonic bursts in the upper limbs, with a myogenic appearance. A muscle biopsy was performed and confirmed the diagnosis of necrotizing autoimmune myopathy. The patient showed improvements after treatment with intravenous immunoglobulin and corticosteroid therapy. Then, the patient was successfully treated with subcutaneous methotrexate, which controlled the disease and demonstrated its value as maintenance treatment. This case highlights the importance of screening for rare myopathies in patients suffering from cancer with myalgias and muscle weakness and the importance of electroneuromyogram and magnetic resonance imaging in the early onset of symptoms to make the correct diagnosis.

The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study.

Elevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia. This multi-center, prospective study enrolled patients aged 3-216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed. Overall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001). Questioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases. Clinicaltrials.gov NCT04120168.

Elevated Creatine Phosphokinase in a Patient on a Long-Acting Antipsychotic: A Challenging Presentation Similar to Neuroleptic Malignant Syndrome.

Elevated Creatine Phosphokinase in a Patient on a Long-Acting Antipsychotic: A Challenging Presentation Similar to Neuroleptic Malignant Syndrome.

P04.01.B MEK INHIBITORS IN PEDIATRIC RECURRENT SYMPTOMATIC UNRESECTABLE LOW-GRADE GLIOMAS HARBORING MAPK ALTERATION: A SINGLE CENTER EXPERIENCE

Abstract BACKGROUND Treatment of inoperable, recurrent, progressive pediatric low-grade gliomas (pLGGs) remains controversial. Recent studies focused on aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, due to gain of function mutations in RAS or BRAF genes or loss or inactivation of NF1. Selumetinib and trametinib, orally bioavailable and selective MEK1/MEK2 inhibitors (MEKi), act on MAPK pathway. In April 2020 the US Food and Drug Administration and in June 2021 the European Medicines Agency approved selumetinib for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi efficacy and safety in pLLGs harboring MAPK alteration. MATERIAL AND METHODS From July 2021 to February 2023 eight patients (5 females, 3 males, median age 8 years, range 4-18) were admitted to our hospital for symptomatic, recurrent, inoperable pLGGs (location: 3 hypothalamic-optic chiasm region, 2 posterior fossa, 1 temporo-mesial, 1 quadrigeminal plate, 1 diffuse leptomeningeal; MAPK alteration: 3 NF1 inactivation, 4 KIAA1549/BRAF gene fusion, 1 RNF130/BRAF fusion). MEKi were administered (6 selumetinib, 2 trametinib) after disease progression for failure of previous treatments (6 partial resection, 7 multiple chemotherapies, 2 radiotherapy). MRI assessment was performed every 4 months and radiological response was defined in accordance with RAPNO criteria. RESULTS At first evaluation, 3/8 patients (37,5%) showed a partial radiological response (-64,96% mean volume reduction, range 52,61%-77,19%) and 4/8 (50%) stable disease (0-41.67% volume decrease). Disease progression was observed in a patient heavily pretreated for acute leukemia. One patient with leptomeningeal spreading showed progressive disease at second evaluation. Median time to progression has not yet been reached. Six of 8 patients experienced at least one toxicity. The most frequent toxicities reported were mucocutaneus disorders (rash, mucositis, eczema). Three patients presented creatine phosphokinase (CPK) increase (one grade 2 with rapid normalization after therapy discontinuation). All patients on trametinib had to reduce treatment dose (for skin toxicity or increasing blood pressure). CONCLUSION MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash. Further studies are needed to identify patients who may benefit most from MEKi treatment and to establish whether such treatments are superior to chemotherapy in front line setting for MAPK altered pLGGs.

Rosuvastatin-induced myopathy in a case of undiagnosed Vitamin D deficiency

For patients who qualify, statins are among the most frequently prescribed drugs for the primary and secondary prevention of cardiovascular disease. A wide range of clinical manifestations, from generalized muscle aches to severe necrotizing myositis, are present in statin-induced myopathy. Here, we present a case of a 49-year-old woman with Vitamin D deficiency who developed statin-induced myopathy 45 days after starting rosuvastatin. A 49-year-old female was admitted to the hospital with a history of lower back pain and bilateral lower limb pain for 7 days. Her ongoing medications include ticagrelor 90 mg BD, metoprolol 25 mg OD, nicorandil 5 mg BD, telmisartan 20 mg OD, dapagliflozin 10 mg OD, metformin 1000 mg OD, vildagliptin 100 mg OD, pantoprazole 40 mg OD, and rosuvastatin 40 mg OD, which were started 45 days back when she was diagnosed with ischemic heart disease. On neurological evaluation, muscle weakness was present in the lower extremities with proximal muscle involvement more than the distal muscle, power at the hip was 2/5, knee and ankle joint were 4/5, knee and ankle reflex were 2/5, and the plantar reflex was normal, with no upper limb involvement. Laboratory investigation on the day of admission revealed elevated creatine phosphokinase (9873.00 U/L) and serum creatinine (2.45 mg/dl). Arterial blood gas analysis revealed a high anion gap with increased lactate levels. Vitamin D levels were found to be insufficient, and serum calcium was in the low normal range. Magnetic resonance imaging of the bilateral lower limb revealed bilaterally symmetrical abnormal edematous signal in muscles of the gluteal region, extensor, adductor, and flexor compartment indicative of myopathy. Volitional testing revealed the presence of spontaneous activity, and an electromyography study revealed that the interference pattern was complete with early recruitment, similar to what is seen in inflammatory myopathy. The motor unit action potential was polyphasic with short duration and amplitude. She was diagnosed with statin-induced myopathy with acute kidney injury. In this case, initiation of rosuvastatin and Vitamin D deficiency were the only positive associated factors that were responsible for myopathy and acute kidney injury and liver injury. Despite the reported incidence of myopathy and renal toxicity by rosuvastatin in the present era, rosuvastatin holds a major market across the globe. Although the case was successfully treated by withholding rosuvastatin, it added to significant morbidity and health-care costs. Therefore, this case report not only calls for increased pharmacovigilance when prescribing rosuvastatin but also adds to the already existing safety controversies surrounding this drug.