Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm

Ocular immune-related adverse events (IrAEs) associated with use of checkpoint inhibitors (CPIs) in cancer therapeutics are relatively rare, occurring in approximately 1% of treated patients. Recognition and early intervention are essential because the degree of tissue damage may be disproportionate to the symptoms, and lack of appropriate treatment risks permanent loss of vision. International guidelines on managing ocular IrAEs provide limited advice only. Importantly, local interventions can be effective and may avoid the need for systemic corticosteroids, thereby permitting the continuation of CPIs. We present a single institution case series of eight affected patients managed by our multidisciplinary team. Consistent with previously published series and case reports, we identified anterior uveitis as the most common ocular IrAE associated with CPIs requiring intervention. Based on our experience, as well as published guidance, we generated a simple algorithm to assist clinicians efficiently manage patients developing ocular symptoms during treatment with CPIs. In addition, we make recommendations for optimising treatment of uveitis and address implications for ongoing CPI therapy.

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Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211560 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2061-2064 ◽

Cited By ~ 73

Author(s):

Sang Taek Kim ◽

Jean Tayar ◽

Van Anh Trinh ◽

Maria Suarez-Almazor ◽

Salvador Garcia ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Case Reports ◽

Unmet Need ◽

Case Series ◽

Receptor Antibody ◽

Improved Outcomes ◽

Clinical Scenarios ◽

Significant Clinical Improvement ◽

Tnfα Inhibitor ◽

Factor Α

BackgroundImmune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with numerous cancers. However, these therapies are associated with immune-related adverse events (irAEs), which are inflammatory side effects potentially affecting any organ. Cases of ICI-induced inflammatory arthritis have also been reported. In general, mild irAEs are treated with corticosteroids, while tumour necrosis factor-α (TNFα) inhibitors are reserved for refractory cases. However, prolonged use of TNFα inhibitor (TNFαi) can induce widespread, significant immunosuppression, which can negatively impact the antitumour efficacy of ICI therapy. Therefore, in clinical scenarios where patients develop severe immunotherapy-induced irAEs, an unmet need exists for alternative therapeutic strategies that are effective and without immune dampening effects.Case reportsThe anti-interleukin (IL)−6 receptor antibody, tocilizumab, is a biological agent Food and Drug Administration approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Here, we report on three patients who developed severe polyarthritis while receiving ICI therapy and were treated with tocilizumab. All three patients demonstrated significant clinical improvement; one patient maintained a durable antitumour response derived from checkpoint inhibition.ConclusionsThese three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFαi for the treatment of arthritis irAEs.

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Rheumatic immune-related adverse events from checkpoint inhibitor therapy: a case series

Beyond Rheumatology ◽

10.4081/br.2021.65 ◽

2021 ◽

Vol 3 (2) ◽

Cited By ~ 1

Author(s):

Antonella Laria ◽

Alfredomaria Lurati ◽

Laura Castelnovo ◽

Antonio Tamburello ◽

Paola Maria Faggioli ◽

...

Keyword(s):

Adverse Events ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Case Series ◽

Hematologic Malignancies ◽

Checkpoint Inhibitor Therapy ◽

Cancer Immunotherapies ◽

Cell Death Protein

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and its ligand PD-L1 are established cancer immunotherapies for solid tumor and hematologic malignancies. These therapies are involved in immune-related adverse events (irAE), both general and rheumatic ones. In general, immune-related adverse events (irAE) management includes drug-holding, tapering doses of corticosteroids, and specific immunosuppression for clinically severe cases, such as infliximab or mycophenolate.

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Real-world risk of anosmia with cancer directed systemic therapy: A pharmacovigilance assessment using FDA Adverse Events Reporting System (FAERS) database.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18790 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18790-e18790

Author(s):

Anahat Kaur ◽

Shuai Wang ◽

Arlene Yu ◽

Tarek N. Elrafei ◽

Lewis Steinberg ◽

...

Keyword(s):

Adverse Events ◽

Reporting System ◽

Case Reports ◽

Descriptive Analysis ◽

Package Insert ◽

Case Series ◽

The United States ◽

Chemotherapeutic Agents ◽

United States Food ◽

Pharmacovigilance Database

e18790 Background: Anosmia is a rare and under-reported adverse event associated with the use of several oncologic drugs. Instances of olfactory disturbances following administration of chemotherapeutic agents have been sporadically documented in case reports and case series. We aimed to conduct a more comprehensive study to generate signal for anosmia as adverse effect of drugs used for oncologic indications. Methods: The United States Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database, a pharmacovigilance database, was used to extract data. All reported cases of anosmia in the database were filtered for an indication of cancer. Descriptive analysis was conducted using SPSS 26. Results: Total 10250 cases of anosmia were extracted from FAERS database. Out of these, cancer as an indication for medication use was noted in 139 cases. Some of the most common suspect medications exclusively associated with more than one case of anosmia were palbociclib (n=16), enzalutamide (13), pazopanib (8), cabozantinib (8), letrozole (6), leuprolide (5), niraparib (5), rucaparib (4), tamoxifen (4), capecitabine (3), everolimus (3), anastrazole (2), exemestane (2), zoledronic acid (2), vandetanib (2) and vismodegib (2). Detailed description of medications with highest number of reported cases is listed in Table. Median age at diagnosis was 66 years (interquartile range 58-71). Anosmia was reported more commonly in females (64% ) as compared to males (33.8%). Reactions were reported to the FDA more commonly by consumers (56.8%) as compared to healthcare professionals (40.3% cases). Out of 139 patients with anosmia, 93 (66.9%) had concomitant ageusia, 8 (5.7 %) had dysgeusia and 6 (4.3%) patients had neuropathy. Conclusions: This study demonstrates a signal for anosmia as side effect in patients receiving select oncologic medications based on the FAERS database. It is worth noting that none of the suspect medications identified in this study have anosmia listed as known adverse reaction on accompanying package insert. Further studies need to be conducted to confirm if causal relationship exists between use of these drugs and olfactory function compromise. [Table: see text]

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Therapeutic potential of pyruvate therapy for patients with mitochondrial diseases: a systematic review

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018820938240 ◽

2020 ◽

Vol 11 ◽

pp. 204201882093824

Author(s):

Min Li ◽

Shuang Zhou ◽

Chaoyang Chen ◽

Lingyun Ma ◽

Daohuang Luo ◽

...

Keyword(s):

Plasma Level ◽

Adverse Events ◽

Mitochondrial Disease ◽

Rating Scales ◽

Rating Scale ◽

Therapeutic Potential ◽

Case Reports ◽

Case Series ◽

Mitochondrial Diseases ◽

Cochrane Library

Background: Mitochondrial disease is a term used to describe a set of heterogeneous genetic diseases caused by impaired structure or function of mitochondria. Pyruvate therapy for mitochondrial disease is promising from a clinical point of view. Methods: According to PRISMA guidelines, the following databases were searched to identify studies regarding pyruvate therapy for mitochondrial disease: PubMed, EMBASE, Cochrane Library, and Clinicaltrials. The search was up to April 2019. The endpoints were specific biomarkers (plasma level of lactate, plasma level of pyruvate, L/P ratio) and clinical rating scales [Japanese mitochondrial disease-rating scale (JMDRS), Newcastle Mitochondrial Disease Adult Scale (NMDAS), and others]. Two researchers independently screened articles, extracted data, and assessed the quality of the studies. Results: A total of six studies were included. Considerable differences were noted between studies in terms of study design, patient information, and outcome measures. The collected evidence may indicate an effective potential of pyruvate therapy on the improvement of mitochondrial disease. The majority of the common adverse events of pyruvate therapy were diarrhea and short irritation of the stomach. Conclusion: Pyruvate therapy with no serious adverse events may be a potential therapeutic candidate for patients with incurable mitochondrial diseases, such as Leigh syndrome. However, recent evidence taken from case series and case reports, and theoretical supports of basic research are not sufficient. The use of global registries to collect patient data and more adaptive trial designs with larger numbers of participants are necessary to clarify the efficacy of pyruvate therapy.

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The Safety of Yoga: A Systematic Review of Case Reports and Case Series on Adverse Events Associated with Yoga

The Journal of Alternative and Complementary Medicine ◽

10.1089/acm.2014.5051.abstract ◽

2014 ◽

Vol 20 (5) ◽

pp. A21-A21

Author(s):

Holger Cramer ◽

Carol Krucoff ◽

Gustav Dobos

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Case Reports ◽

Case Series

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Detect it so you can treat it: a case series and proposed checklist to detect neurotoxicity in checkpoint therapy

10.21203/rs.3.rs-19760/v1 ◽

2020 ◽

Author(s):

Saskia Bolz ◽

Thivyah Ramakrishnan ◽

Michael Fleischer ◽

Elisabeth Livingstone ◽

Benjamin Stolte ◽

...

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Case Series ◽

Transverse Myelitis ◽

University Hospital ◽

Life Threatening ◽

Checkpoint Inhibitor Therapy ◽

Cancer Types ◽

Brachial Plexus Neuritis

Abstract Background: Checkpoint inhibitors show impressive and durable responses in various cancer types and provide new avenues for cancer immunotherapy. However, these drugs have a variety of adverse events. Common autoimmune-related adverse effects include fatigue, hepatitis, skin rash, endocrine deficiencies, and colitis. Neurotoxicity has been reported, but its incidence and course remain unclear.Methods: To illustrate the broad spectrum of neurotoxicity, we exemplarily report the neurological adverse events of five patients with melanoma and one patient with differentiated thyroid cancer who received checkpoint inhibitors at Essen University Hospital (Essen, Germany).Results: After treatment with ipilimumab, nivolumab or pembrolizumab, neurotoxic effects included hypophysitis-associated neck pain and headache, Guillain-Barré syndrome, transverse myelitis, acute brachial plexus neuritis, and ocular myasthenia gravis.Conclusions: Checkpoint inhibitor therapy remains a success story; however, neurological immune-related adverse events may cause severe life-threatening conditions. We propose a checklist for the early detection of neurological adverse events during routine clinical treatment to prevent more severe courses of checkpoint inhibitor-induced neurotoxicity.

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Repurposing of drugs for Covid-19: a systematic review and meta-analysis

10.1101/2020.06.07.20124677 ◽

2020 ◽

Cited By ~ 1

Author(s):

Pinky Kotecha ◽

Alexander Light ◽

Enrico Checcucci ◽

Daniele Amparore ◽

Cristian Fiori ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Adverse Events ◽

Clinical Improvement ◽

Case Reports ◽

Meta Analysis ◽

Case Series ◽

Cochrane Library ◽

Control Group ◽

Significant Difference

AbstractObjectiveThe aim of this systematic review is to evaluate the data currently available regarding the repurposing of different drugs for Covid-19 treatment. Participants with suspected or diagnosed Covid-19 will be included. The interventions being considered are drugs being repurposed, and comparators will include standard of care treatment or placebo.MethodsWe searched Ovid-MEDLINE, EMBASE, Cochrane library, clinical trial registration site in the UK(NIHR), Europe (clinicaltrialsregister.eu), US (ClinicalTrials.gov) and internationally (isrctn.com), and reviewed the reference lists of articles for eligible articles published up to April 22, 2020. All studies in English that evaluated the efficacy of the listed drugs were included. Cochrane RoB 2.0 and ROBINS-I tool were used to assess study quality. This systematic review adheres to the PRISMA guidelines. The protocol is available at PROSPERO (CRD42020180915).ResultsFrom 708 identified studies or clinical trials, 16 studies and 16 case reports met our eligibility criteria. Of these, 6 were randomized controlled trials (763 patients), 7 cohort studies (321 patients) and 3 case series (191 patients). Chloroquine (CQ) had a 100% discharge rate compared to 50% with lopinavir-ritonavir at day 14, however a trial has recommended against a high dosage due to cardiotoxic events. Hydroxychloroquine (HCQ) has shown no significant improvement in negative seroconversion rate which is also seen in our meta-analysis (p=0.68). Adverse events with HCQ have a significant difference compared to the control group (p=0.001). Lopinavir-ritonavir has shown no improvement in time to clinical improvement which is seen in our meta-analyses (p=0.1). Remdesivir has shown no significant improvement in time to clinical improvement but this trial had insufficient power.DiscussionDue to the paucity in evidence, it is difficult to establish the efficacy of these drugs in the treatment of Covid-19 as currently there is no significant clinical effectiveness of the repurposed drugs. Further large clinical trials are required to achieve more reliable findings. A risk-benefit analysis is required on an individual basis to weigh out the potential improvement in clinical outcome and viral load reduction compared to the risks of the adverse events. (1-16)

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Total Ankle Replacement in Hemophilia

Cardiovascular & Haematological Disorders - Drug Targets ◽

10.2174/1871529x19666191210110626 ◽

2020 ◽

Vol 20 (2) ◽

pp. 88-92

Author(s):

Emerito C. Rodriguez-Merchan

Keyword(s):

Adverse Events ◽

Daily Living ◽

Case Reports ◽

Case Series ◽

Total Ankle Replacement ◽

Cochrane Library ◽

Hemophilic Arthropathy ◽

Accessible Information ◽

Ankle Replacement

Introduction: Severe ankle hemophilic arthropathy can be a calamitous sign of severe hemophilia with important inferences for activities of daily living. Aims: To summarize the contemporary, accessible information on Total Ankle Replacement (TAR) for ankle hemophilic arthropathy. Methods: A search of Cochrane Library and PubMed (MEDLINE) regarding the role of TAR in ankle hemophilic arthropathy. Results: The insufficient information regarding the results of TAR for hemophilic arthropathy is confined to scanty case series and case reports. An evaluation of the accessible literature reveals encouraging but inconstant outcomes. The reported rate of adverse events is 33%. The reported anticipated survival of TAR is 94% at 5 years, 85% at 10 years and 70% at 15 years. Conclusion: Whereas people with advanced hemophilic arthropathy of the ankle are prone to ameliorate pain and range of motion following TAR, there is deficient knowledge to regularly recommend its use. Adverse events and infection percentages are disturbing. Moreover, the lack of survival analysis knowledge makes it difficult to assess the benefit to people with hemophilia. TAR is a demanding surgical procedure and its survival is not comparable to that after hip or knee replacement.

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Real-world outcomes of immune-related adverse events in 2,125 patients managed with immunotherapy: A United Kingdom multicenter series.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.7065 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 7065-7065

Author(s):

Anna Claire Olsson-Brown ◽

Mark Baxter ◽

Caroline Dobeson ◽

Laura Feeney ◽

Rebecca Lee ◽

...

Keyword(s):

Health Service ◽

Adverse Events ◽

Real World ◽

Management Strategies ◽

Case Series ◽

Systemic Corticosteroids ◽

Ct Data ◽

Clinically Significant ◽

Uk National Health Service ◽

The Uk

7065 Background: Immune-related adverse events (irAE) are a recognised complication of immune checkpoint inhibitor (ICI) therapy. Previous characterisation of irAEs has been limited to clinical trial or registry populations and small case series. Here we present a multi-centre, granular, real-world analysis of the prevalence and outcomes of irAEs experienced by patients managed within a single comprehensive public health service. Methods: A multi-centre retrospective analysis of 2125 consecutive patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or combination therapy (CT). Data were collected using a standardised, pre-piloted, collection tool. IrAEs ≥ grade 2 or endocrinopathies of any grade were considered clinically significant and recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Descriptive statistics were employed using Stata v15 (College Station, TX). Results: Patients received αPD-1 (1757; 82%), combination αPD-1/αCTLA-4 (285, 13%), αCTLA-4 (51; 2%) and αPD-L1 (31; 1%) immunotherapy for malignant melanoma (961), non-small cell lung cancer (788) or renal cell carcinoma (335). The median age was 66 (MT) and 57 (CT). Clinically significant irAEs occurred in 732 (34%) individuals; 28% (524) on MT and 73% (208) on CT. Colitis (206,10%), thyroiditis (194, 9%), hepatitis (142, 7%) and dermatitis (126, 6%) were most commonly observed. Grade 1 endocrinopathies occurred in 20% (173) of cases. Grade 2 irAEs occurred in 43% (359), grade 3 31% (269) and grade 4 6% (51). The were 3 (0.4%) cases of grade 5 irAE; pneumonitis (2) and hepatitis, all following αPD-1 MT. 93% (680) required corticosteroids with 64% (490) requiring systemic corticosteroids and 11% (80) steroid sparing immunosuppression. 16% (336) of patients had pre-existing autoimmune disease of whom 40% (136) experienced irAEs. IrAEs led to admission in 42% (308) of cases, accounting for 2996 bed days. Length of stay was 7 days (1-67; IQR 4-13). Higher dependency care was required in 0.7% (15) of cases. Colitis (35%, 107) and hepatitis (25%, 77) accounted for the most admissions. Pneumonitis accounted for 3% (66) of irAEs but 12% of admissions. Conclusions: One third of patients experienced a clinically-significant irAE resulting in significant morbidity and admission burden highlighting the need for effective management strategies to optimise patient outcomes.

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