Musculoskeletal Adverse Events Research Articles

Comparison of the Clinical Efficacy of Rituximab Infusion and Dexamethasone-Cyclophosphamide Pulse Therapy and Their Effect on Serum Th1, Th2, and Th17 Cytokines in Pemphigus Vulgaris–A Prospective, Nonrandomized, Comparative Pilot Study

Abstract Background: Rituximab infusion and dexamethasone-cyclophosphamide pulse (DCP) are the two most popular regimens used in pemphigus vulgaris (PV) in India. Objective: The present study compared the clinical efficacy of rituximab and DCP in Indian PV patients and their effects on serum Th1,2, and 17 cytokine levels. Materials and Methods: A total of 37 patients received DCP (Group A, n = 22) or rituximab (Group B, rheumatoid arthritis protocol (n = 15)) as per patients’ preference. They were monitored for clinical response, adverse events (AEs), changes in serum anti-desmoglein-1,3 antibody titers and Th1,2 and 17 cytokine levels at baseline and weeks 20 and 52. Results: The proportion of patients attaining disease control, remission, and relapse in groups A and B were 82% and 93%; 73% and 93%; and 27% and 50%, respectively, after a median duration of 2 months each for disease control; 4 and 4.5 months for remission; and 5 and 7 months for relapse post remission. The musculoskeletal AEs were the highest in the two groups. Significant and comparable decreases in anti-dsg1 and 3 titers from baseline to weeks 20 and 52 were observed in both groups. Th1 and Th17 cytokine levels decreased, while Th2 cytokines increased post-treatment in both groups. However, no correlation was found between change in body surface area of involvement by PV and anti-dsg titers and cytokine levels before and after therapy in both groups. Conclusion: Comparable clinical efficacy between DCP and rituximab was observed.

COVID-19 Vaccine in Immunosuppressed Adults with Autoimmune rheumatic Diseases (COVIAAD): safety, immunogenicity and antibody persistence at 12 months following Moderna Spikevax primary series

ObjectiveTo assess the safety, immunogenicity and cellular responses following the Moderna Spikevax primary series in rheumatic disease.MethodsWe conducted a 12-month, prospective, non-randomised, open-label, comparative trial of adults with either rheumatoid...

Musculoskeletal adverse events induced by immune checkpoint inhibitors: a large-scale pharmacovigilance study.

Background: The musculoskeletal toxicity of immune checkpoint inhibitors (ICIs) is receiving increasing attention with clinical experience. Nevertheless, the absence of a systematic investigation into the musculoskeletal toxicity profile of ICIs currently results in the under-recognition of associated adverse events. Further and more comprehensive investigations are warranted to delineate the musculoskeletal toxicity profile of ICIs and characterize these adverse events. Material and methods: The present study employed the FDA Adverse Event Reporting System database to collect adverse events between January 2010 and March 2021. We utilized both the reporting odds ratio and the Bayesian confidence propagation neural network algorithms to identify suspected musculoskeletal adverse events induced by ICIs. Subsequently, the clinical characteristics and comorbidities of the major musculoskeletal adverse events were analyzed. The risk of causing these events with combination therapy versus monotherapy was compared using logistic regression model and Ω shrinkage measure model. Results: The musculoskeletal toxicity induced by ICIs primarily involves muscle tissue, including neuromuscular junctions, fascia, tendons, and tendon sheaths, as well as joints, spine, and bones, including cartilage. The toxicity profile of PD-1/PD-L1 and CTLA-4 inhibitors varies, wherein the PD-1 inhibitor pembrolizumab exhibits a heightened overall risk of inducing musculoskeletal adverse events. The major ICIs-induce musculoskeletal adverse events, encompassing conditions such as myositis, neuromyopathy (including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Guillain-Barré syndrome, and Chronic inflammatory demyelinating polyradiculoneuropathy), arthritis, fractures, myelitis, spinal stenosis, Sjogren's syndrome, fasciitis, tenosynovitis, rhabdomyolysis, rheumatoid myalgia, and chondrocalcinosis. Our study provides clinical characteristics and comorbidities of the major ICIs-induced musculoskeletal adverse events. Furthermore, the combination therapy of nivolumab and ipilimumab does not result in a statistically significant escalation of the risk associated with the major musculoskeletal adverse events. Conclusion: Immune checkpoint inhibitors administration triggers a range of musculoskeletal adverse events, warranting the optimization of their management during clinical practice.

OA15 IL-13 inhibition used for atopic diseases is associated with risk of psoriatic arthritis

Abstract Background/Aims Inhibitors of the IL-13 pathway, such as dupilumab and tralokinumab, are licensed to treat atopic diseases such as eczema and asthma. Musculoskeletal adverse events that resemble enthesitis and psoriatic arthritis (PsA) after dupilumab initiation have been reported, but evidence is limited to case reports and spontaneous pharmacovigilance with uncertain causal inference. Naturally occurring genetic variation in drug targets can provide insight into their potential adverse effects. We used population-level data to investigate whether genetically proxied IL-13 inhibition (IL-13i) increases risk of PsA and other spondyloarthritis-related diseases. Methods Dupilumab is recognised to reduce eosinophil count in clinical studies; we therefore used it as the biomarker of IL-13i. We instrumented IL-13i using missense (protein coding) variants within the IL13 gene that are associated with circulating eosinophil count at genome-wide significance (p < 5x10-8) in a study of 563,946 individuals. Outcome genetic associations were taken from studies of PsA, psoriasis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and iritis. To examine instrument validity, we used atopic eczema and asthma as positive control outcomes, and rheumatoid arthritis as a negative control. We used the ratio method, with estimates scaled to per standard deviation (SD ∼0.14x109/L) reduction in eosinophil count. Results One missense variant, rs20541, was selected to proxy IL-13i. Genetically proxied IL-13i was associated with increased risk of PsA (OR 37.39; 95%CI 11.52, 121.34), psoriasis (OR 20.08; 4.38, 92.01), Crohn’s disease (OR 3.49; 1.38, 8.81), but not ulcerative colitis, ankylosing spondylitis or iritis. IL-13i was associated with reduced risk of positive control outcomes, but not with the negative control (Table 1). Conclusion Genetically proxied IL-13 inhibition is associated with increased risk of PsA, psoriasis and Crohn’s disease, which may be a class effect relevant to other IL-13i that are not yet reported to have Th17-type adverse events. These findings are compatible with the hypothesis that Th2 cytokines IL-4/-13 may act as a restraint toward Th17-type disease activation in some organs. Clinicians assessing adverse events after dupilumab initiation should be aware of incident PsA and related features. This study demonstrates the value of MR in evaluating rare adverse events in the study of drug safety. Disclosure S. Zhao: None. K.L. Hyrich: None. Z.Z.N. Yiu: None. A. Barton: None. J. Bowes: None.

Musculoskeletal immune-related adverse events in 927 patients treated with immune checkpoint inhibitors for solid cancer.

The prevalence of the musculoskeletal immune-related adverse events (irAEs) is probably underestimated, as most studies report only severe side effects. Our aim was to describe and characterize all musculoskeletal irAEs in a large cohort of patients treated with immune checkpoint inhibitors (ICI). We conducted a retrospective study among patients who received ICI from 07/27/2014 to 05/08/2020 at the medical oncology department of the Institut Paoli-Calmettes, Marseille, France. All medical files were systemically reviewed by a rheumatologist who collected clinical features, time of occurrence, treatment regimen, irAEs management, course and outcomes. We also assessed tumor response 3 months after introduction of ICI, according to severity and treatments used to manage musculoskeletal irAEs. Among 927 patients treated with ICI for a solid tumor, 118 patients (12.7%) presented a musculoskeletal irAE. Their median age was 66.5, 61% were male, and they mainly had a lung (57.6%) or urological cancer (27.1%). The most frequently involved ICI was an anti PD-1. Arthralgias and myalgias were the most frequent musculoskeletal irAEs (9.8%) and inflammatory rheumatic features were reported in 36 patients (3.9%) with elevated acute phase reactants and negative immunological markers. The median time of onset was 2 months (IC95% 1.8; 2.7). Tumor response at 3 months did not differ according to musculoskeletal irAE severity, type of manifestation (arthralgias/myalgias versus inflammatory rheumatic features), pain patterns (mechanical versus inflammatory) or irAE treatments. Musculoskeletal irAEs in this large cohort of patients treated with ICI were frequent (12.7%), mostly mild and well tolerated.

The Debut of Inflammatory Musculoskeletal Pathology in Patients Receiving Anticancer Therapy with PD-1/PD-L1 Pathway Inhibitors

Objective: to describe musculoskeletal immune-mediated adverse events (iAEs) associated with the therapy of solid tumors with immune checkpoint inhibitors (ICIs, inhibitors of the PD-1/PD-L1 pathway).Patients and methods. 13 patients receiving ICIs therapy with musculoskeletal iAEs were examined. The average age of patients was 59±10 years. All cases had a histologically verified diagnosis of a malignant solid neoplasm: melanoma (n=5), kidney cancer (n=3), bladder cancer (n=2), non-small cell lung cancer (n=1), breast cancer (n=1), cervical cancer (n=1). All patients were prescribed inhibitors of the PD-1/PD-L1 signaling pathway: nivolumab (n=6), pembrolizumab (n=3), atezolizumab (n=3), prolgolimab (n=1). In 7 (54%) patients, in addition to musculoskeletal disorders, other AEs were also detected: thyroiditis (n=3), neuropathy (n=2), rash (n=1), dry syndrome (n=1), hepatitis (n=1). The median time from the start of antitumor immunotherapy (IT) to the onset of musculoskeletal pathology was 20 [9; 48] weeks.Results and discussion. Clinical manifestations of musculoskeletal pathology included: synovitis in 9 (69%) patients, tenosynovitis in 11 (85%), enthesitis in 4 (31%), morning stiffness in the joints for more than 30 minutes in 4 (31%). In 11 cases, musculoskeletal pathology was persistent (in 9 patients with arthritis and 2 with periarthritis) and in 2 – transient. The knee (77%), shoulder (69%) and hand (54%) joints were most frequently affected, with bilateral involvement in 9 (69%) patients. Inflammatory changes in the joints were represented by mono- (n=1), oligo- (n=3) and polyarthritis (n=5), including those involving the small joints of the hands and/or feet (n=5) and predominantly affecting the joints of the lower limbs (n=3). In 3 patients with arthritis, periarticular changes dominated in clinical picture (in 2 patients with symmetrical polyarthritis and severe tenosynovitis, in another 1 patient – with RS3PE syndrome). The severity of musculoskeletal pathology was assessed using the CTCAE v5.0 toxicity criteria: grade 1 was documented in 2 (15.5%), grade 2 in 9 (69%), and grade 3 in 2 (15, 5%) patients. Laboratory workup revealed elevation of ESR ≥30 mm/h (median – 34 [14; 42] mm/h) in 7 out of 12 (58%) patients, elevation of CRP level >5 mg/l (median – 7.2 [4.6; 12.9] mg/l) – in 7 out of 10 (70%). In 7 out of 10 patients, antinuclear antibodies (Hep2) were detected in titers: 1:160 (n=2), 1:320 (n=3), 1:640 (n=2). Rheumatoid factor and antibodies to cyclic citrullinated peptide were not detected in any case. Therapy for musculoskeletal AEs included non-steroidal anti-inflammatory drugs (n=10), oral systemic glucocorticoids – GC (n=5), methotrexate – MT (n=1) and hydroxychloroquine (n=5), intra-articular administration of GC (n=1). Five patients with arthritis required long-term therapy (median duration – 12 [3; 12] months), in 1 patient with polyarthritis and severe tenosynovitis, antitumor IT was interrupted for the duration of the course of MTX treatment.Conclusion. It has been shown that musculoskeletal iAEs have heterogeneous manifestations and may require long-term treatment and in rare cases, anticancer therapy interruption. Additional studies and close cooperation between rheumatologists and oncologists are needed to obtain a more complete understanding of the nature and spectrum of musculoskeletal AEs, to identify their clinical, laboratory and instrumental features, and to develop an management of patients algorithm.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Growth analysis among adolescents with moderate-to-severe atopic dermatitis receiving upadacitinib in combination with topical corticosteroids in Japan: A case study series from a phase 3, randomized, controlled trial (Rising Up)

BackgroundTreatment options for adolescents with moderate-to-severe atopic dermatitis (AD) are limited. Oral corticosteroid therapies are used to treat children and adolescents with moderate-to-severe AD; however, long-term use is not recommended because of potential growth impairment. Upadacitinib, an oral Janus kinase inhibitor, is approved to treat moderate-to-severe AD in the United States, Japan, and Europe. To investigate potential effects of upadacitinib on growth, we analyzed height and height velocity in 6 adolescent patients in the phase 3 Rising Up study who were in the decline phase of pubertal growth at the time of study entry. MethodsThe randomized, double-blind, Rising Up (NCT03661138) study compared upadacitinib plus topical corticosteroids (TCS) to placebo plus TCS in adolescents and adults with moderate-to-severe AD in Japan. Eligible adolescents (aged 12–17 years) were randomized 1:1:1 to receive once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo in combination with TCS for 16 weeks. After 16 weeks, patients randomized to receive placebo were rerandomized 1:1 to receive upadacitinib 15 mg or upadacitinib 30 mg. Historical height measurements were obtained when available. Individual growth and growth velocity curves were compared with standard curves for Japanese youths. This non-prespecified analysis used 52-week data. ResultsOf the 29 adolescents enrolled, 6 were in the decline phase of pubertal growth at enrollment. Growth curves and growth velocity curves for these 6 patients remained within the normal range for Japanese adolescents throughout the study. Biomarkers of bone metabolism generally remained stable over the course of the study. No musculoskeletal adverse events were reported. ConclusionsNo cases suggested that upadacitinib negatively affected adolescent growth. Ongoing studies will continue to assess height and adverse effects related to bone growth to further inform on this patient group. Trial registrationClinicalTrials.gov Identifier NCT03661138.

Aromatase inhibitors for breast cancer therapy: Analysis of real-world FAERS data.

1051 Background: Aromatase inhibitors (AIs) are extremely effective adjuvant treatment in postmenopausal women with hormone receptor-positive breast cancer (HRPBC). We utilized the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate the musculoskeletal (MSK), fractures, and ischemic heart disease (IHD) adverse events (AEs) caused by AIs. Methods: We conducted a retrospective FAERS public database review to assess the MSK, fracture, and IHD AEs for the three AIs (anastrozole, letrozole, and exemestane) from 2001 through 2021. Chi-square was used to compare categorical variables. Results: A total of 31,683 AEs reports were identified, out of which, 15,140 (47.8%) were MSK, 13,311 (42.0%) were fracture, and 3,232 (10.2%) were IHD. The differences in AEs distributions among the three drug classes were statistically significant for MSK and fracture AEs (P < 0.001) but not reached statistical significance for IHD AEs (P = 0.140). MSK AEs were mostly reported with anastrozole, followed by exemestane, and letrozole in 35.23%, 33.97%, and 32.06%, respectively (P < 0.001). Compared to older individuals, younger adults (≤65 years) had higher rates of MSK AEs—mostly with anastrozole (38.43%, P < 0.001), followed by exemestane (36.37%, P = 0.006) and letrozole (34.28%, P < 0.001). Fracture AEs were mostly reported, in descending order, with letrozole, exemestane, and anastrozole in 12.07%, 11.41%, and 9.34% respectively (P < 0.001). Older adults (> 65 years) had higher rates of fracture AEs with letrozole (16.77%, P < 0.001) and anastrozole (10.37%, P < 0.001), while unable to demonstrate statistical significance with exemestane (13.48%, P = 0.108). Among older adults (> 65 years), IHD AEs were significantly reported with anastrozole (21.56%, P < 0.001) and exemestane (14.18%, P = 0.016) but no statistical significance reached for letrozole (14.12%, P = 0.528). Conclusions: The findings in this study highlight trends for selected AEs with various AI regimens, provide further insights, and help guide therapeutic decisions for patients with HRPBC.

Ethnic disparities in adverse events of chemotherapy for breast cancer: A scoping review.

e18524 Background: Ethnic disparities may contribute to a higher symptom burden of adverse events following chemotherapy and poorer response to treatment for breast cancer. The objective was to examine the intra-group and inter-group ethnic differences in adverse effects experienced by Asian breast cancer patients undergoing chemotherapy with aromatase inhibitors or tamoxifen. Methods: A scoping review involving the Pubmed database was conducted. The search strategy included a combination of keywords and index terms related to Asians, breast cancer, CTCAE and treatment. Title, abstract and then full-text screening was performed by two reviewers. Primary research studies and systematic review articles involving female adults in peer-reviewed articles or grey literature records, of any design or date and published in English, were included. Descriptive statistics and charting was used to summarize the results. Results: Of 1765 abstracts retrieved and screened, 56 articles were ultimately included for analysis. Most articles (58.9%) studied the adverse events of tamoxifen. The majority of the studies involved Japanese patients (35.7%) followed by Chinese patients (19.6%) with an average of 8515 patients being studied per study. Only 2 studies were conducted in the US. Half the studies (50%) involved patients with TNM stage I breast cancer, postoperatively enrolled after BCS or mastectomy (71.4%). ER/PR status was reported in 58.9% of studies with an average of 494 patients being positive for either hormone receptor. HER-2 status was reported in 10 studies with an average of 53 positive HER-2 patients. 28.5% of studies involved patients with musculoskeletal adverse events following chemotherapy with aromatase inhibitors, commonly grade 3 or above (31.2%). These adverse events were arthralgia, fractures, osteoporosis or myalgia, affecting an average of 33.9% of patients in each study. 35.7% of studies involved patients with endocrinological adverse events following chemotherapy with tamoxifen. These adverse events involved menopausal symptoms, gynecological complications or endometrial cancer, affecting an average of 36.1% of patients in each study. Conclusions: Multi-level differences may contribute to the adverse events affecting Asian breast cancer patients undergoing chemotherapy with aromatase inhibitors or tamoxifen. Improving physician knowledge of ethnic disparities in adverse events occurring in Asian ethnic subgroups can help improve overall outcomes and patient adherence through a patient-centered approach.

Immunotherapy for Management of Thymic Epithelial Tumors: A Double-Edged Sword.

Simple SummaryImmunotherapy has a rapidly expanding role for the treatment of several cancers due to durable clinical activity and favorable tolerability. However, the unique biology of thymic epithelial tumors (TETs) increases the risk of immune-mediated toxicity. In this paper we review the biology of thymic cancers and its impact on the potential benefits and risks of immunotherapy. We describe the results of completed clinical trials of immune checkpoint inhibitors for advanced TETs and provide an overview of potential biomarkers of response or toxicity of immunotherapy that might influence future development of immunotherapeutic modalities for the treatment of advanced thymoma and thymic carcinoma.Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The occurrence of paraneoplastic autoimmune disorders in patients with TETs, especially thymomas, creates significant challenges for the development of immunotherapy, including immune checkpoint inhibitors, as a feasible treatment option. In addition, patients with TETs are at increased risk for the development of immune-mediated toxicity with a predilection for musculoskeletal and neuromuscular adverse events upon treatment with immunotherapy. The identification of biomarkers of response and toxicity is expected to play a key role in harnessing the benefits of immunotherapy for patients with TETs. In this paper we review the biology of TETs and the potential effects on the tolerability of immunotherapy. The results of clinical trials of immune checkpoint inhibitors for the treatment of advanced TETs are described to understand the potential risks and benefits of immunotherapy. We also provide an overview of future avenues for treatment with novel immunotherapeutic modalities and opportunities to develop biomarkers to improve the safety and tolerability of immunomodulatory treatments in patients with TETs.

Ontology-Based Classification and Analysis of Adverse Events Associated With the Usage of Chloroquine and Hydroxychloroquine.

Multiple methodologies have been developed to identify and predict adverse events (AEs); however, many of these methods do not consider how patient population characteristics, such as diseases, age, and gender, affect AEs seen. In this study, we evaluated the utility of collecting and analyzing AE data related to hydroxychloroquine (HCQ) and chloroquine (CQ) from US Prescribing Information (USPIs, also called drug product labels or package inserts), the FDA Adverse Event Reporting System (FAERS), and peer-reviewed literature from PubMed/EMBASE, followed by AE classification and modeling using the Ontology of Adverse Events (OAE). Our USPI analysis showed that CQ and HCQ AE profiles were similar, although HCQ was reported to be associated with fewer types of cardiovascular, nervous system, and musculoskeletal AEs. According to EMBASE literature mining, CQ and HCQ were associated with QT prolongation (primarily when treating COVID-19), heart arrhythmias, development of Torsade des Pointes, and retinopathy (primarily when treating lupus). The FAERS data was analyzed by proportional ratio reporting, Chi-square test, and minimal case number filtering, followed by OAE classification. HCQ was associated with 63 significant AEs (including 21 cardiovascular AEs) for COVID-19 patients and 120 significant AEs (including 12 cardiovascular AEs) for lupus patients, supporting the hypothesis that the disease being treated affects the type and number of certain CQ/HCQ AEs that are manifested. Using an HCQ AE patient example reported in the literature, we also ontologically modeled how an AE occurs and what factors (e.g., age, biological sex, and medical history) are involved in the AE formation. The methodology developed in this study can be used for other drugs and indications to better identify patient populations that are particularly vulnerable to AEs.

Association Between Statin Use and Daptomycin-related Musculoskeletal Adverse Events: A Mixed Approach Combining a Meta-analysis and a Disproportionality Analysis.

BackgroundThere is a growing concern about the association between the combined use of daptomycin (DAP) and statins and the occurrence of musculoskeletal adverse events (MAEs), but this remains controversial. This study aimed to clarify the association between statin use and DAP-related MAEs.MethodsWe used a mixed approach that combines 2 methodologies. First, we conducted a meta-analysis to examine the effects of statin use on DAP-related MAEs. Second, we conducted a disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to further confirm the results of the meta-analysis and to examine the effect of each type of statin on DAP-related MAEs in a large population.ResultsIn the meta-analysis, statin use significantly increased the incidence of DAP-related rhabdomyolysis (odds ratio [OR]: 3.83; 95% confidence interval [CI]: 1.43–10.26) but not DAP-related myopathy (OR: 1.72; 95% CI: .95–3.12). In the disproportionality analysis using the FAERS, the use of statin significantly increased the reporting OR (ROR) for DAP-related myopathy (ROR: 5.69; 95% CI: 4.31–7.51) and rhabdomyolysis (ROR: 5.77; 95% CI: 4.33–7.68). Atorvastatin, rosuvastatin, and simvastatin all increased the incidence of DAP-related myopathy and rhabdomyolysis.ConclusionThe mixed approach combining a meta-analysis and disproportionality analysis showed that statin use was associated with the occurrence of DAP-related rhabdomyolysis. The appropriate use of statins and DAP should be performed with careful consideration of its safety.

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.

PCSK9 inhibitors associated with increase in musculoskeletal adverse events

PCSK9 inhibitors associated with increase in musculoskeletal adverse events

Musculoskeletal Adverse Events Associated with PCSK9 Inhibitors: Disproportionality Analysis of the FDA Adverse Event Reporting System.

Background Some studies suggest that potential safety issues about PCSK9 inhibitors have not been sufficiently explored in clinical trials, including musculoskeletal adverse events (MAEs). Objective To examine the association between use of PCSK9 inhibitors with and without concurrent statins and risk of MAEs. Patients and Methods. FDA Adverse Event Reporting System (FAERS) dataset of PCSK9 inhibitors and statins from October 2015 to June 2021 was queried. The reporting odds ratio (ROR) with relevant 95% confidence interval (95% CI) was calculated as the index of disproportionality. Outcome of MAEs of different PCSK9 inhibitors regimens was also investigated. Results 3,185 cases of PCSK9 inhibitor-associated MAEs were recorded. PCSK9 inhibitor class alone demonstrated a strong link to MAEs (ROR 5.92; 95% CI 5.70-6.15), and evolocumab was associated with more reports of MAEs than alirocumab. Concomitant use with statins leaded to an increased occurrence of MAEs (ROR 32.15 (25.55-40.46)), and the risk differed among different statins. The PCSK9 inhibitors were safer than statins in terms of hospitalization rate and death rate (15.64% vs. 36.83%; 0.72% vs. 3.53%). Conclusions This pharmacovigilance investigation suggests that PCSK9 inhibitors are associated with MAEs. The risk significantly increases when combined with statins. Increased laboratory and clinical monitoring are required to timely diagnose and manage MAEs.

A Phase I/II Study of Bosutinib in Pediatric Patients with Resistant/Intolerant or Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia, Study ITCC (Innovative Therapies for Children with Cancer European Consortium) 054 and COG (Children's Oncology Group Consortium) AAML1921: Results from the Phase I Trial in Resistant/Intolerant Patients

A Phase I/II Study of Bosutinib in Pediatric Patients with Resistant/Intolerant or Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia, Study ITCC (Innovative Therapies for Children with Cancer European Consortium) 054 and COG (Children's Oncology Group Consortium) AAML1921: Results from the Phase I Trial in Resistant/Intolerant Patients

Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria

IntroductionPrimary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles.MethodsNonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition.ResultsBased on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function.ConclusionPhase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.

Parenteral Cyanocobalamin Induced Arthralgia: A Case Report

: Cyanocobalamin is a presently coenzyme mainly involved in reactions leading to synthesis of Nucleic Acids and of that of methionine from homocysteine. On the other hand hematological neurological and epithelial clinical manifestations observed during Vitamin B12 deficiency may lead to Pernicious anemia. Pernicious anemia is a megaloblastic anemia which leads to abnormal erythrocyte nuclear maturation and leading to ultimate effect of loss of adequate stores of the Vitamin B12. Arthralgia induced after / following cobalamin administration is rarely. Despite of that various drugs are known to cause musculoskeletal adverse events such as arthralgia, myalgia and serum sickness. We present a Case of a 54 Year Old Male, with chief complaint of fever, pallor skin, shortness of breath and tiredness. On the fifth day, patient develops cyanocobalamin induced arthralgia and main treatment of the drug induced arthralgia is the discontinuation of the responsible drug. However patients can be managed with one active form of Vitamin B12 which is methyl cobalamin that has excellent beneficial therapeutic management for Joint Pain. In this case report a rare adverse event of Vitamin B12 Injection inducing arthralgia is reported.Key words: DIA, Vitamin B12, Arthralgia, Naranjo Probability Scale, Adverse Drug Reaction.

Adverse event clusters present at dose-reduction in CLL patients on ibrutinib in the U.S. Veterans Health Administration.

252 Background: Previously, we reported that adverse events (AEs) were the top reason for dose reductions in VHA patients on novel agents. Some AEs might be problematic but might not directly lead to dose reduction; however, these concomitant AEs should not be overlooked. This study describes AE clusters that occurred with the primary AE that led to dose reduction in VHA CLL patients receiving ibrutinib. Methods: This is a retrospective chart review study of CLL patients treated with ibrutinib in the VHA from October 2013 to March 2018. Variables included the presence of dose reduction, the reasons for dose reduction, primary AEs leading to dose reduction, and concomitant AEs present at the time of dose reduction. Descriptive statistics were used to summarize AE clusters. Results: Out of 1069 CLL patients on ibrutinib, 285 patients experienced dose reduction due to AEs and were included in this analysis. The most common AEs leading to dose reduction were: musculoskeletal (11%), bleeding (11%), fatigue (10%), infection (9%), atrial fibrillation (8%), diarrhea (8%), and rash (8%). Fatigue was the leading concomitant AE present at dose reduction among patients who were dose reduced due to musculoskeletal (18%), infection (12%), diarrhea (18%), and rash (25%). Fatigue was also the second-leading or third leading concomitant AE among those who were dose reduced due to atrial fibrillation (13%) or bleeding (10%). Musculoskeletal was the leading or second-leading concomitant AE present at dose reduction among those who were dose reduced due to fatigue (17%), infection (12%), or diarrhea (14%). Bleeding was the leading concomitant AE among those who were dose reduced due to atrial fibrillation (17%) and vice versa. Conclusions: This study provides evidence that fatigue and musculoskeletal AEs are problematic in CLL patients on ibrutinib in the VHA. These were not only among the most common primary AEs but also the leading concomitant AEs present at dose reduction. Although not directly leading to dose reduction, these ‘nuisance’ AEs can greatly affect quality of life among CLL patients and warrant more attention from clinicians. A better understanding of all AEs present at dose reduction may help clinicians better manage patients on novel agents. These data also highlight the unmet need for novel agents with a ‘cleaner’ safety profile.