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Validation of International Classification of Diseases Code–Based Case Definitions of Immune Checkpoint Inhibitor–Associated Inflammatory Arthritis From Administrative Health Data

Objective Immune checkpoint inhibitors (ICIs) for cancer can lead to immune-related adverse events, including ICI-associated inflammatory arthritis (ICI-IA). There are no validated International Classification of Diseases (ICD) code–based case definitions for ICI-IA. Methods We conducted a validation study using the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) database. Rheumatologist-confirmed ICI-IA was the reference standard, defined as new onset of at least one swollen joint on examination or synovitis on imaging following ICI exposure, without another cause or pre-existing IA. We compared ICD-9 (714.x and 696.0) and ICD-10 (M05.x, M06.x, and M07.x) IA diagnostic codes against the reference standard. Seven core case definitions of different combinations of ICD codes from the Physician Claims Database (PCD) and the Discharge Abstract Database were tested. Results were stratified by sex. Sensitivity testing with additional criteria was also evaluated. Results We included 228 patients in the final analysis: 100 with ICI-IA and 128 without ICI-IA. Sensitivity of the tested case definitions ranged from 1.0% to 88.0%, whereas specificity ranged from 86.7% to 100.0%. The case definition with at least one PCD IA code achieved the best balance of sensitivity (88.0%, 95% confidence interval [CI] 81.6%–94.4%) and specificity (86.7%, 95% CI 80.8%–92.6%). Case definition performances were similar between sexes. Additional criteria minimally improved specificity but sacrificed sensitivity. Conclusion ICD code–based case definitions of ICI-IA can accurately detect ICI-IA and can be used to support ICI-IA surveillance and research with administrative health data.

CRA/CanRIO Living Guidelines for Baseline Immunosuppression in Individuals with Preexisting Rheumatic Diseases Initiating Immune Checkpoint Inhibitors. Part 2: Preexisting Systemic Autoimmune Rheumatic Diseases.

Objective: Although immune checkpoint inhibitors (ICIs) are increasingly used in patients with preexisting systemic autoimmune rheumatic diseases (SARDs), a key concern is whether baseline immunosuppression at the start of ICI treatment might negatively affect cancer outcomes. This risk must be carefully weighed against the potential for a SARD flare. The objective of this study was to develop a living guideline that will provide up-to-date guidance on the management of baseline immunosuppression for preexisting SARDs when initiating cancer immunotherapy with ICIs. Methods: The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) formed a multidisciplinary panel composed of rheumatologists, oncologists, researchers, and a patient representative, with methodological support from the Canadian Rheumatology Association (CRA). We completed a systematic literature review to inform this first installment of our living guideline. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, the panel developed recommendations for the management of baseline immunosuppression in individuals with preexisting SARDs. Results: We identified 67 publications that reported on immunosuppression and cancer outcomes by specific preexisting rheumatic diseases, including 36 on preexisting SARD. Eight best practice statements were developed, highlighting the importance of shared decision making between patients and their care team and careful consideration of risk of SARD flare, risk of organ- or life-threatening manifestations, and potential effect of immunosuppression on cancer outcomes. Seven specific recommendations were made, 1 each for preexisting systemic lupus erythematosus, systemic sclerosis, Sjögren disease, myositis, sarcoidosis, vasculitis, and Behçet disease, considering both the available evidence and expert consensus. The general recommendation for preexisting SARDs was to continue baseline immunosuppression, particularly if there are organ- or life-threatening manifestations. Conclusion: This living guideline will provide contemporary baseline immunosuppression recommendations for individuals with cancer and preexisting SARDs when initiating ICI therapy. New recommendations will be added over time and updated, with the latest recommendations, evidence summaries, and Evidence to Decision summaries available through the CRA and CanRIO websites (www.rheum.ca, www.canrio.ca). (PROSPERO registration: CRD42023461024).

Chronicity of Immune Checkpoint Inhibitor-Associated Inflammatory Arthritis After Immunotherapy Discontinuation: Results From the Canadian Research Group of Rheumatology in Immuno-Oncology Database

Objective: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) and progression-free survival (PFS) in many types of malignancies but can result in off-target immune-related adverse events including inflammatory arthritis (ICI-associated inflammatory arthritis [ICI-IA]), which can persist even after ICI cessation. We aimed to examine the proportion of patients with ICI-IA who develop chronic ICI-IA and describe characteristics and outcomes associated with chronic ICI-IA. Methods: We identified patients from the Canadian Research Group of Rheumatology in Immuno-Oncology retrospective cohort who developed de novo ICI-IA with at least three months of follow-up after ICI cessation. Chronic ICI-IA was defined as symptoms or ongoing immunosuppression lasting beyond three months after ICI discontinuation. Acute ICI-IA was defined as resolution of ICI-IA symptoms and discontinuation of immunosuppression within three months of ICI discontinuation. OS and PFS were assessed with Kaplan-Meier curves. Landmark multivariable Cox proportional hazard models for OS and PFS were conducted. Results: The study cohort included 119 patients. A total of 15 patients (13%) had acute ICI-IA, whereas 104 (87%) had chronic ICI-IA. Patients with chronic ICI-IA were more likely to be White and to have polyarthritis at presentation. After adjusting for age, sex, tumor type, stage of cancer, ICI-IA treatment, and time from ICI initiation to ICI-IA onset, patients with chronic ICI-IA had greater PFS from ICI initiation (adjusted hazard ratio 0.27, 95% confidence interval 0.08-0.98; P = 0.046). Adjusted hazard ratio for OS was similar between those with acute versus chronic ICI-IA. Conclusion: ICI-IA frequently persists after ICI discontinuation. Chronic ICI-IA is associated with improved PFS, but not OS, as compared to acute ICI-IA.

CRA/CanRIO Living Guidelines for Baseline Immunosuppression in Individuals with Pre-existing Rheumatic Diseases Initiating Immune Checkpoint Inhibitors. Part 1: Preexisting Inflammatory Arthritides.

Objective: Immune checkpoint inhibitors (ICIs) are being increasingly used in patients with preexisting inflammatory arthritides (IAs). However, there are concerns that concomitant baseline immunosuppression at the time of ICI initiation may worsen cancer outcomes, a risk that needs to be balanced with the risk of IA flare. The objective of this study was to develop a living guideline that will offer up-to-date guidance on the management of baseline immunosuppression for preexisting IAs when initiating cancer immunotherapy with ICIs. Methods: The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) formed a multidisciplinary panel composed of rheumatologists, oncologists, researchers, and a patient representative, with methodological support from the Canadian Rheumatology Association (CRA). We completed a systematic literature review to inform this first installment of our living guideline. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, the panel developed recommendations for the management of baseline immunosuppression in individuals with preexisting IAs. Results: We identified 67 relevant publications that reported on immunosuppression and cancer outcomes by specific preexisting rheumatic diseases, including 44 on preexisting IA. Eight best practice statements were developed, highlighting the importance of shared decision making between patients and their care team and careful consideration of risk of IA flare, risk of organ- or life-threatening manifestations, and the potential effect of immunosuppression on cancer outcomes. Four specific recommendations were made, one each for preexisting rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthritis, and spondyloarthritis, considering both the available evidence and expert consensus. The general recommendation for preexisting IAs was to reduce or stop baseline immunosuppression, unless there are extraarticular organ- or life-threatening manifestations. Conclusion: This living guideline will provide contemporary baseline immunosuppression recommendations for individuals with cancer and preexisting IA when initiating ICI therapy. New recommendations will be added over time and updated, with the latest recommendations, evidence summaries, and Evidence to Decision summaries available through the CRA and CanRIO websites (www.rheum.ca, www.canrio.ca). (PROSPERO registration: CRD42023461024).

Acrocyanosis After Immunotherapy: Vasculitis or Vasculopathy? New Iatrogenic Disease Case Series From CanRIO

Improving Knowledge Dissemination of Rheumatic Toxicities of Cancer Immunotherapy: A Web‐Based Educational Initiative

Effect of Age on Rheumatic Immune-Related Adverse Events: Experience From the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO)

Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer outcomes but are limited by immune-related adverse events (irAEs), including rheumatic irAEs (Rh-irAEs). Aging is associated with increased inflammation, referred to as "inflammaging." In this study, we explore the effect of age on severity, frequency, and treatment of Rh-irAEs. Methods: Adults with new Rh-irAEs after ICI exposure are followed prospectively across 10 Canadian sites as part of the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) prospective cohort. In this study of patients seen between January 2020 and March 2023, we compare the severity of Rh-irAEs and number of irAEs between patients aged ≥ 65 years and < 65 years and explore potential epidemiologic, treatment-related, and phenotypic differences between the older and younger patients. Results: A total of 139 patients with de novo Rh-irAEs were included, 58 in the younger (aged < 65 yrs) and 81 in the older (aged ≥ 65 yrs) group. There were no significant differences in severity of Rh-irAEs (P = 0.84) or number of irAEs (P = 0.21), although there was a nonsignificant trend toward more younger patients than older patients with ≥ 3 irAEs (24% vs 14%). Types of treatment for Rh-irAEs were similar between the groups. ICI continuation did not differ. Within the ICI-related inflammatory arthritis subgroup, there was also no significant difference in the incidence of severe Rh-irAEs (P = 0.51). Conclusion: Similar numbers of overall irAEs and severity of Rh-irAEs were observed between older vs younger patients who developed Rh-irAEs after treatment with ICI therapy, suggesting that inflammaging does not play a significant role in Rh-irAEs. Larger studies are needed to explore potential differences in patient phenotypes.

Osteoporotic fractures: an unrecognized adverse event of immune checkpoint inhibitors?

The widespread use of immune checkpoint inhibitors (ICIs) in clinical practice has broadened our understanding of their immune-related adverse events (irAEs). IrAEs, including musculoskeletal adverse events, remain a significant concern. While ICI-associated arthritis is a well-documented musculoskeletal side effect of ICI therapy, the direct effects of ICIs on bone in patients with cancer are poorly understood. There is emerging evidence to support the hypothesis that ICIs adversely impact bone turnover and can lead to osteoporosis and fragility fractures, which are not currently recognized as irAEs.

The Utility of Laboratory Investigations for the Assessment and Management of Rheumatic Immune Related Adverse Events

Immune checkpoint inhibitors (ICIs) have greatly improved survival of several cancers with historically very poor prognosis. ICIs act by stimulating the patient's own immune system to fight cancer. Simultaneously, this immune activation can lead to immune-related adverse events (irAEs), including rheumatic manifestations (Rh-irAEs). Rh-irAEs mimic primary rheumatic diseases including arthritis, polymyalgia rheumatica, myositis, vasculitis, sarcoidosis, and sicca. This article summarizes the latest evidence regarding the utility of laboratory investigations in Rh-irAEs.

False-positive Findings of Large Vessel Vasculitis on FDG-PET in Patients Treated With Immune Checkpoint Inhibitors

Fluorine-18 fluorodeoxygluocose positron emission tomography (FDG-PET) is increasingly used in the evaluation of response to immune checkpoint inhibitor (ICI) therapy. Incidental findings of increased vessel wall uptake may prompt the concern for ICI-induced large vessel vasculitis (LVV). Precise radiographic and clinical evaluation is required to determine if this represents true vasculitis, as use of immune suppression and ICI discontinuation can have significant impacts on patient outcomes. We performed a retrospective case analysis of 4 consecutive patients referred to 2 rheumatology clinics treated with ICI with incidental findings of LVV on FDG-PET, reviewing their clinical course and radiographic findings. All 4 cases had FDG-PET scans for routine oncology indications and had no associated clinical features of LVV. One patient was treated with corticosteroids and no patients developed any clinical evidence of vasculitis during a mean follow-up period of 17 months (range: 7-33 mo). All FDG-PET images reporting LVV underwent a standardized analysis to identify any technical issues or concerns with interpretation. In review of imaging, 3 of the cases may have been due to delayed tracer to scan interval leading to misinterpretation of vascular uptake as suspected LVV. Recognition of technical pitfalls in FDG-PET interpretation is crucial to inform the need for immunosuppression and the safety of continued ICI therapy.

De novo Connective Tissue Disorders as Immune-related Adverse Events.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment through blocking immunoregulatory pathways, resulting in augmented antitumor responses. However, ICIs can cause inflammatory autoimmune toxicities, known as immune-related adverse events (irAEs). Common rheumatic irAEs include inflammatory arthritis, polymyalgia rheumatica-like symptoms, and myositis. Fewer cases of de novo connective tissue disease as irAEs have been described and have mainly presented with cutaneous manifestations of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Treatments include glucocorticoids and steroid-sparing agents such as hydroxychloroquine, mycophenolate mofetil, and methotrexate with improvement of symptoms. In this review, the authors discuss immune-related SLE and SSc and their management.

Musculoskeletal immune-related adverse events of PD-(L)1 inhibitors in melanoma: a systematic review and meta-analysis

Background: Immune checkpoint inhibitors (ICIs) are first-line treatment for melanoma. The incidence of musculoskeletal immune-related adverse events (MSK irAEs) remains unclear. Objective: To estimate the relative risk of MSK irAEs in melanoma patients treated with ICIs targeting programmed cell death-1 or its ligand PD-(L)1 as compared to placebo. Methods: We performed a systematic literature review including phase III randomized controlled trials of adult melanoma patients comparing a PD-(L)1 inhibitor to a placebo arm. Outcomes of interest included arthralgias, arthritis, back pain and myalgias. Meta-analysis was performed to estimate the pooled relative risk of MSK irAEs over the treatment course. Results: Four RCTs met the inclusion criteria (n = 3,041 subjects). Use of PD-(L)1 inhibitors was associated with an increased risk of developing arthralgias (RR 1.30 [95% CI: 1.13-1.49]) and myalgias (RR 1.48 [95% CI: 1.17-1.87]) as compared to placebo. Back pain and arthritis were not reported. Conclusions: Use of PD-(L)1 inhibitors is associated with a significantly increased risk of arthralgias and myalgias in melanoma patients. The risk of back pain and arthritis is unknown. Implications for practice: MSK irAEs can impact quality of life and should be considered, particularly in the adjuvant setting when risks and benefits are carefully weighed.

Preexisting autoimmune disease and immune-related adverse events associated with anti-PD-1 cancer immunotherapy: a national case series from the Canadian Research Group of Rheumatology in Immuno-Oncology

Background: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). Methods: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. Results: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. Conclusion: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.

Immune-related Adverse Events Associated with Cancer Immunotherapy: A Review for the Practicing Rheumatologist

Immune checkpoint inhibitors have revolutionized cancer therapy by blocking inhibitory pathways of the immune system to fight cancer cells. Their use is often limited by the development of autoimmune toxicities, which can affect multiple organ systems and are referred to as immune-related adverse events (irAE). Among these are rheumatologic irAE, including inflammatory arthritis, myositis, vasculitis, and others. Rheumatologic irAE seem to be different from irAE in other organs and from traditional autoimmune diseases in that they can occur early or have delayed onset, and can persist chronically, even after cancer therapy is terminated. Because immune checkpoint inhibitors are increasingly used for many types of cancer, it is important for oncologists and rheumatologists to recognize and manage toxicities early. In this review, we discuss currently approved immune checkpoint inhibitors and their mechanisms of action and systemic toxicities, with a focus on the management and effect on further cancer therapy of rheumatic irAE.

Rheumatic immune-related adverse events associated with cancer immunotherapy: A nationwide multi-center cohort

Objective: Although immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, their use is associated with immune toxicities referred to as immune-related adverse events (irAE). Here we describe the clinical presentation and management of rheumatic immune-related adverse events (Rh-irAE) in a national multi-center cohort. Methods: All patients presenting with Rh-irAE at 9 academic sites across Canada between January 2013 and January 2019 were identified and included in this retrospective cohort study. Standardized data were extracted by chart review. Results: 117 patients who developed 136 Rh-irAE were identified. The most frequent Rh-irAE was symmetric polyarthritis (n = 45). Other Rh-irAE included non-inflammatory musculoskeletal symptoms (n = 18), polymyalgia rheumatica (n = 17) and myositis (n = 9). Prednisone was the most commonly used treatment (n = 76) with a mean maximum dose of 60 ± 74 mg/d and duration of treatment of 8.4 ± 11 months. Forty-two patients required conventional synthetic disease-modifying anti-rheumatic drugs (DMARD) and two required biologic DMARD to control the Rh-irAE. ICI was discontinued due to the Rh-irAE in 22 patients. There were no deaths related to Rh-irAE. Treatment of the Rh-irAE did not appear to negatively impact the tumor response to immunotherapy with 23 patients experiencing tumor progression prior to treatment of the Rh-irAE and 13 following treatment. Conclusion: In this largest multi-center cohort of Rh-irAE described to date, symmetric polyarthritis was the most common Rh-irAE. There was considerable heterogeneity of treatment, although this did not appear to negatively impact the anti-tumor response. This study can inform the development of evidence-based recommendations to optimize Rh-irAE and cancer outcomes in patients treated with ICI.