Noha Abdel-Wahab

Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports

Background Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported. Objectives To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity. Data Sources We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015. Study Selection Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included. Data Extraction We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes. Data Synthesis 191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab. Limitations Our study is limited by information available in the original reports. Conclusions Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported.

Review: Immune-Related Adverse Events With Use of Checkpoint Inhibitors for Immunotherapy of Cancer

Major advances in the past 2 decades have enhanced our understanding of the complex interactions between the immune system and cancer cells and their environment. Genetic and epigenetic alterations in tumor cells result in diverse antigenic expression that can elicit an immune response, primarily mediated by T cells. Immune responses are regulated by stimulatory, costimulatory, and inhibitory (checkpoint) signals. Inhibitory signals play an important role in self-tolerance under normal conditions. In the presence of tumor cells, immune checkpoint pathways can be disrupted, resulting in tumoral immune resistance. In the past few decades, several approaches have been proposed to enhance host antitumor responses. Among the most salient strategies is the use of monoclonal antibodies against regulatory immune checkpoint molecules that inhibit T cell activation (1). These agents up-regulate the immune function by blocking checkpoint inhibition, resulting in durable tumor responses in patients with metastatic disease that are not seen with traditional chemotherapy. Nonetheless, despite its impressive therapeutic benefits, checkpoint blockade can induce profound inflammatory and immune-related adverse events (AEs), which can be severe and limit use of checkpoint inhibition (2). Tumor immunity

Immune-Related Adverse Events with the Use of Checkpoint Inhibitors for Immunotherapy of Cancer

Major advances in the past 2 decades have enhanced our understanding of the complex interactions between the immune system and cancer cells and their environment. Genetic and epigenetic alterations in tumor cells result in diverse antigenic expression that can elicit an immune response, primarily mediated by T cells. Immune responses are regulated by stimulatory, costimulatory, and inhibitory (checkpoint) signals. Inhibitory signals play an important role in self-tolerance under normal conditions. In the presence of tumor cells, immune checkpoint pathways can be disrupted, resulting in tumoral immune resistance. In the past few decades, several approaches have been proposed to enhance host antitumor responses. Among the most salient strategies is the use of monoclonal antibodies against regulatory immune checkpoint molecules that inhibit T cell activation (1). These agents up-regulate the immune function by blocking checkpoint inhibition, resulting in durable tumor responses in patients with metastatic disease that are not seen with traditional chemotherapy. Nonetheless, despite its impressive therapeutic benefits, checkpoint blockade can induce profound inflammatory and immune-related adverse events (AEs), which can be severe and limit use of checkpoint inhibition (2). Tumor immunity

Adverse events in cancer immunotherapy

Cancer immunotherapy has resulted in durable responses in patients with metastatic disease, unseen with traditional chemotherapy. Several therapies have been approved by the Food and Drug Administration for the treatment of various cancers, including: immune checkpoint inhibitors, cytokines - interleukin 2 (IL-2) and interferon alpha (IFN), and the cancer vaccine sipuleucel-T. These therapies upregulate the immune system to enhance antitumor responses. As a consequence, they can cause inflammatory and immune-related adverse events that can affect one or more organs, can be serious, and on occasion lifethreatening. The management of these adverse events is complex, and requires a multidisciplinary approach involving not only oncologists, but also other internal medicine specialists, to ensure prompt diagnosis and optimal management of these complications.

Myositis as an adverse event of immune checkpoint blockade for cancer therapy

OBJECTIVES Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis. METHODS We identified patients with myositis who were receiving ICIs between January 2004 and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS Six patients developed de novo myositis. The mean age was 64.3 years and five patients were male. Cancer types included melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer. ICI regimens included single-agent ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and ipilimumab (n = 3). The median time to development of de novo myositis from first infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them developed rhabdomyolysis, one with concurrent myocarditis. Five patients were treated with 1-2mg/kg corticosteroids, with variable response rates; one patient received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as a result of cancer progression. CONCLUSION We found several occurrences of de novo myositis following ICI therapy. These preliminary data suggest that myositis can occur early after onset of ICI therapy with serious adverse outcomes.

Association of hand grip strength with disease activity, disability and quality of life in children and adolescents with Juvenile Idiopathic Arthritis

BackgroundJuvenile idiopathic arthritis (JIA) affects wrist and hand joints leading to decrease hand function and patients’ daily living activities. The assessment of hand grip strength (HGS) in children and adolescents with JIA is of major importance, and the association of HGS with JIA disease activity, disability and quality of life has not been explored. The primary objective of this study was to evaluate hand grip strength (HGS) in children and adolescents with Juvenile Idiopathic Arthritis (JIA) compared to matched healthy peers. The secondary objective was to explore the relationship between HGS and JIA disease activity, disability, and quality of life.MethodsThis study involved 23 patients with JIA and 46 age and sex matched healthy controls. Hand held dynamometer was used to evaluate HGS for all study participants. Anthropometric parameters for all study participants were measured. Disease activity, physical function, and quality of life were assessed for the JIA group using juvenile arthritis disease activity score (JADAS-27), juvenile arthritis functionality scale (JAFS), and pediatric quality of life inventory (PedsQL) respectively. Laboratory marker of inflammation, erythrocyte sedimentation rate (ESR), and plain radiography of hands were performed for all patients.ResultsHand grip strength of children and adolescents with JIA was significantly weaker compared to matched controls (p < 0.001). Hand grip strength had a significant inverse correlation with JADAS-27 (r = − 0.467, p = 0.025), JAFS (r = − 0.650, p = 0.001) and a significant direct correlation with PedsQL (r = 0.438, p = 0.036). In addition, HGS was negatively correlated with ESR and duration of morning stiffness (r = − 0.489, p = 0.018 and r = − 0.201, p = 0.359, respectively). HGS was detected as an independent predictor of disease activity, disability, and quality of life in JIA patients in multivariate linear regression.ConclusionsAssessment of HGS could be a simple non-invasive tool for assessing disease activity, disability and quality of life in JIA patients in clinical practice.

FRI0552 Hand Grip Strength as Simple Predictor of Disease Activity and Disability in Patients with Juvenile Idiopathic Arthritis

Background Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease resulting in joints arthritis and deformities in the hands and fingers. This leads to decrease of joint mobility and strength of the hands which can lead to physical and functional hand disability (1) and subsequent reduction in daily living activities (2). Despite the presence of indices to assess the hand function, grip strength assessment remains the strong predictor of both hand and upper limb function (3). Hand grip strength (HGS) can be measured quantitatively using a hand dynamometer (4). Although the role of HGS in evaluating hand function in JIA has been studied (5), the use of HGS as a predictor of disease activity and disability in JIA has not been explored. Objectives The aim of the study was to evaluate the HGS in JIA patients using electronic hand dynamometer and to assess its relationship with JIA disease activity, disability and quality of life. Methods Twenty-three patients with JIA (14 girls and 9 boys) diagnosed according to International League of Associations for Rheumatology (ILAR) classification criteria and 59 healthy children were enrolled in the study. The disease activity was assessed using Juvenile Disease Activity Score (JDAS-27). Juvenile Arthritis Functionality Scale (JAFS) and Pediatric QOL Inventory (PedsQL) were used to assess physical function and quality of life respectively. HGS was tested 3 times in each hand of every patient and control using electronic hand dynamometer and the mean value was considered. Results Patients with JIA showed low HGS in one or both hands compared with healthy children (p=0.001). Grip strength showed a significant inverse correlation with JDAS-27 (p=0.003, r value = -0.591) and with JAFS (total and after exclusion of hand component) (p=0.001 and 0.002, r value = -0.650 and -0.608 respectively). Significant correlations were observed between HGS and PedsQL (p=0.036). Conclusions Patients with JIA have reduced HGS when compared to healthy children. HGS may be considered as a non invasive predictor of JIA disease activity and disability. Pediatric quality of life is adversely affected with decrease in HGS. HGS testing might be used a simple screening for disease activity in patients with JIA. References Filocamo G, Sztajnbok F, Cespedes-Cruz A, Magni-Manzoni S, Pistorio A, Viola S, Ruperto N, Buoncompagni A, Loy A, Martini A, Ravelli A (2007) Development and validation of a new short and simple measure of physical function for juvenile idiopathic arthritis. Arthritis Rheum 57 (6) Article: 913-20 Varni JW, Seid M, Kurtin PS (2001) PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 39 (8) Article: 800-12 Dunn W (1993) Grip strength of children aged 3 to 7 years using a modified sphygmomanometer: comparison of typical children and children with rheumatic disorders. Am J Occup Ther 47 (5) Article: 421-8 Sheehy C, Gaffney K, Mukhtyar C (2013) Standardized grip strength as an outcome measure in early rheumatoid arthritis. Scand J Rheumatol Lindehammar H (2003) Hand strength in juvenile chronic arthritis: a two-year follow-up. Acta Paediatr 92 (11) Article: 1291-6 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1858