Incidence of checkpoint inhibitor-associated inflammatory arthritis, immunomodulation and mortality in cancer patients on immunotherapy: a retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitor (ICI) associated inflammatory arthritis (ICI-IA) occurs in 4-6% of ICI-treated patients based on one observational study. We identified cases of ICI-IA using administrative claims to study its incidence and characteristics at the population level. METHODS: We used the Medicare 5% sample to identify patients initiating ICIs. Cancer patients were identified by having ≥ 2 ICD-9/10-CM diagnosis codes from an oncologist for lung cancer, melanoma, or renal/urothelial cancer. ICI-IA was defined as having two Medicare claims ≥ 30 days apart with combinations of ICD-9/10-CM diagnosis codes that favored specificity. ICI-IA was identified in patients with a musculoskeletal diagnosis after ICI initiation, who had i.) no inflammatory arthritis or inflammatory rheumatic disease before ICI initiation ever, and ii) no musculoskeletal complaint in the one year prior to ICI. We examined DMARD utilization and visits to rheumatology in patients with ICI-IA. Landmark analysis and a time varying Cox proportional hazards model for overall survival was constructed. RESULTS: The incidence of ICI-IA was 7.2 (6.1-8.4) per 100 patient years. Patients with ICI-IA were mean (SD) age 73.5(7.0) years, 48% women, 91% white. Median(IQR) time from ICI initiation to first ICI-IA diagnosis was 124(56, 252) days. Only 24(16%) received care from a rheumatologist, and 24(16%) were prescribed a DMARD (46% by a rheumatologist). The HR for mortality in patients with ICI-IA was 0.86 (95% CI 0.59-1.26, p= 0.45). CONCLUSIONS: The incidence of ICI-IA identified in claims data is similar to that reported in observational studies, however, few patients are treated with a DMARD or see a rheumatologist. There was no difference in overall survival between ICI-treated patients with and without ICI-IA.

Autoantibodies in Patients With Immune-Related Adverse Events From Checkpoint Inhibitors: A Systematic Literature Review.

BACKGROUND: Immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) are sometimes associated with autoantibodies, but we do not know how frequently or whether these autoantibodies are present before ICI initiation. Our aim was to determine the positivity rate of autoantibodies in patients with organ-specific ICI-associated irAEs and determine their value as pretreatment biomarkers. METHODS: We searched for all English, peer-reviewed publications from MEDLINE, Embase, and Cochrane Library through February 20, 2020, and included any publication describing patients with irAEs and reporting results of any autoantibody investigation. Three reviewers independently extracted data, and 1 reviewer verified all data for accuracy and quality of reporting. RESULTS: We identified 515 publications. Most reports described endocrine, rheumatic, gastrointestinal/hepatic, and myositis/myasthenia/myocarditis irAEs. Autoantibodies were present in close to 50% of patients with ICI-associated endocrinopathies. Anti-BP180 was found in more than 50% of patients with skin irAEs. Antibodies were also common in patients with the triad of myositis/myasthenia/myocarditis including striational antibodies (49%), acetylcholine receptor antibodies (40%), and myositis-associated antibodies (27%). Only 11% of patients with arthritis had either rheumatoid factor or cyclic citrullinated peptide antibodies, and only 30% of patients with sicca had Sjögren antibodies. Autoantibodies were also relatively uncommon in patients with hepatitis (antinuclear antibody, 18%) and colitis (perinuclear antineutrophil cytoplasmic antibody, 19%). Some cohort studies analyzing pre-ICI seropositivity suggest there may be a role for autoantibodies as biomarkers of irAEs. CONCLUSIONS: Reported autoantibody positivity is high in irAEs involving the endocrine organs, skin, and muscle, but lower in irAEs affecting other organ systems. Autoantibody investigations in pre-ICI treatment patients have yielded mixed results regarding their utility as a biomarker of irAEs.

Checkpoint Inhibitor-Associated Arthritis: A Systematic Review of Case Reports and Case Series.

OBJECTIVE: We performed a systematic literature review to identify all reports of immune checkpoint inhibitor-associated inflammatory arthritis to describe it phenotypically and serologically. METHODS: PubMed, Embase, and Cochrane databases were searched for reports of musculoskeletal immune-related adverse events secondary to ICI treatment. Publications were included if they provided individual patient level data regarding the pattern of joint involvement. Descriptive statistics were used to summarize results. RESULTS: A total of 4339 articles were screened, of which 67 were included, encompassing 372 patients. The majority of patients had metastatic melanoma (57%), and they were treated with anti-PD1 or anti-PDL1 therapy (78%). Median time to onset of arthritis was 4 months (range, 1 day to 53 months). Forty-nine percent had polyarthritis, 17% oligoarthritis, 3% monoarthritis, 10% arthralgia, and 21% polymyalgia rheumatica. More than half of patients were described as having a "rheumatoid arthritis-like" presentation. Nine percent tested positive for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. Seventy-four percent required corticosteroids, and 45% required additional medications. Sixty-three percent achieved arthritis control, and 32% were ultimately able to discontinue antirheumatic treatments. Immune checkpoint inhibitors were continued in 49%, transiently withheld in 11%, and permanently discontinued due to musculoskeletal immune-related adverse events in 13%. CONCLUSIONS: Half of reported immune checkpoint inhibitor-associated arthritis cases present with polyarthritis (often RA-like), but only 9% are seropositive. Polymyalgia rheumatica is also common. Most patients respond to steroids alone, but about half require additional medications. Further studies are needed to determine long-term musculoskeletal outcomes in these patients, and the impact of arthritis treatment on cancer survival.

Impact of Non-steroidal Anti-inflammatory Drugs, Glucocorticoids, and Disease-Modifying Anti-Rheumatic Drugs on Cancer Response to Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitor (ICI) therapy for advanced malignancies often leads to off-target adverse events. Rheumatic immune-related adverse events can often linger beyond the duration of ICI therapy and sometimes requires the use of immunomodulator therapy. A key question, therefore, is if the commonly used therapies affect cancer outcomes. In this review, the authors summarize the state of the data as it currently stands, taking into consideration the limitations of the various source studies. The most information is known about glucocorticoids, which appear to be harmful especially when used early and at high doses.

Anticitrullinated peptide antibody epitope expansion and the HLA DRB1 'shared epitope' are less common in seropositive checkpoint inhibitor-induced inflammatory arthritis than in longstanding rheumatoid arthritis.

BACKGROUND: Immune checkpoint inhibitors (ICI) can potentially cause ICI-inflammatory arthritis (ICI-IA), which often resembles rheumatoid arthritis (RA). In this study, we examined the degree of anticitrullinated peptide antibodies (ACPA) epitope expansion in CCP+ICI-IA and patients with RA. METHODS: We used clinical data and serum from ICI-IA and patients with RA with early disease as well as longstanding disease. A custom, bead-based antigen array was used to identify IgG ACPA reactivities to 18 putative RA-associated citrullinated proteins. Hierarchical clustering software was used to create a heatmap to identify ACPA levels. Additionally, HLA DRB1 typing was performed on ICI-IA patients as well as controls of patients treated with ICI that did not develop ICI-IA (ICI controls). RESULTS: Compared to patients with CCP+RA, patients with CCP+ICI-IA were older (p<0.001), less likely to have positive rheumatoid factor (p<0.001) and had a shorter duration of symptoms (p<0.001). There were less ACPA levels and a lower number of distinct ACPA epitopes in the serum of patients with ICI-IA compared with longstanding patients with RA (p<0.001). Among those tested for HLA DRB1, there were no differences in the frequency of the shared epitope between those with ICI-IA and ICI controls. CONCLUSION: Patients with ICI-IA had lower ACPA titres and targeted fewer ACPA epitopes than longstanding patients with RA, and there were no significant differences in the presence of the shared epitope between those that developed ICI-IA and ICI controls. It remains to be determined if ICI-IA represents an accelerated model of RA pathogenesis with ICI triggering a transition from preclinical to clinical disease.

Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.

Monitoring and Management of the Patient with Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Current Perspectives.

In this review, we draw from observational studies, treatment guidelines and our own clinical experience to describe approaches to monitoring and management of immune checkpoint inhibitor (ICI)-induced inflammatory arthritis, including polymyalgia rheumatica. This condition occurs in about 4% of ICI-treated cancer patients and can persist for a year or longer. Mild arthritis can generally be managed with non-steroidal anti-inflammatory drugs, intraarticular steroids injections and/or low dose corticosteroids. Higher grade arthritis should be brought under control with corticosteroids, but early introduction of a steroid-sparing agent is recommended to minimize steroid toxicity. In order to assess the effectiveness of any arthritis treatment, tender and swollen joint counts and patient reported measures of physical function, such as the health assessment questionnaire, should be obtained at each visit. Referral to a rheumatologist is recommended for patients with high grade arthritis to help guide the use of disease-modifying antirheumatic drugs.

Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are a novel cancer therapeutic that have been successful in treating advanced malignancies; however, they also cause immune-related adverse events (irAE). Given that some irAE are clinically similar to traditional autoimmune diseases, autoantibodies have been suggested as possible biomarkers of irAE. However, there are very little data on autoantibody investigation prior to ICI. Our aim was to determine if specific baseline autoantibodies were associated with irAE and see if changes in autoantibody concentration corresponded with irAE development. METHODS: This study used data from an oncologic clinical trial of adaptive dosing combination ICI therapy in patients with advanced melanoma. Plasma was collected at baseline and 6 weeks after ICI initiation and tested in a microarray of 120 autoantigens commonly associated with autoimmune disease, as well as antinuclear antibody (ANA), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (anti-CCP). Autoantibody concentrations were compared between patients experiencing an organ-specific event versus not. Heatmaps, volcano plots and hierarchical clustering were used to determine autoantibody concentration differences among irAE patient clusters as defined by signal intensity of autoantibodies. Kaplan-Meier curves were created and a log-rank test was performed to assess differences in survival. RESULTS: The microarray analysis demonstrated that patients who experienced specific irAE had fewer differentially expressed autoantibodies at baseline than those that did not have those specific irAE, and a greater fold change (FC) in antibody concentration from baseline to 6 weeks corresponded with specific irAE development. However, no autoantibodies were identified as being predictive of specific events. Time to first irAE was less than 6 weeks in 69% of patients, and these patients had less autoantibodies at baseline. Considering ANA, RF and CCP autoantibodies, there were no significant differences between the seropositive and seronegative patients in irAE development, severity, timing or survival. CONCLUSION: Patients with low autoantibody concentrations at baseline as well as a greater FC in autoantibody concentration over 6 weeks developed more distinct organ-specific irAE. This may suggest differences in the balance of cellular immunity and humoral pathways that are relevant in the pathogenesis of irAE, though further investigation is needed.

Activated osteoarthritis following immune checkpoint inhibitor treatment: an observational study.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can result in toxicities, known as immune-related adverse events (irAEs), due to a hyperactivated immune system. ICI-related inflammatory arthritis has been described in literature, but herewith we introduce and characterize post-ICI-activated osteoarthritis (ICI-aOA). We conducted a multicenter, retrospective, observational study of patients with cancer treated with ICIs and diagnosed with ICI-aOA by a rheumatologist. ICI-aOA was defined by (1) an increase in non-inflammatory joint pain after ICI initiation, (2) in joints characteristically affected by osteoarthritis, and (3) lack of inflammation on exam. Cases were graded using the Common Terminology Criteria for Adverse Events (CTCAE) V.6.0 rubric for arthralgia. Response Evaluation Criteria in Solid Tumors V.1.1 (v.4.03) guidelines determined tumor response. Results were analyzed using χ2 tests of association and multivariate logistic regression. Thirty-six patients had ICI-aOA with a mean age at time of rheumatology presentation of 66 years (51-81 years). Most patients had metastatic melanoma (10/36, 28%) and had received a PD-1/PD-L1 inhibitor monotherapy (31/36, 86%) with 5/36 (14%) combination therapy. Large joint involvement (hip/knee) was noted in 53% (19/36), small joints of hand 25% (9/36), and spine 14% (5/36). Two-thirds (24/36) suffered multiple joint involvement. Three of 36 (8%) had CTCAE grade 3, 14 (39%) grade 2 and 19 (53%) grade 1 manifestations. Symptom onset ranged from 6 days to 33.8 months with a median of 5.2 months after ICI initiation; five patients suffered from ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3, and 15.4 months after ICI cessation). The most common form of therapy was intra-articular corticosteroid injections only (15/36, 42%) followed by non-steroidal anti-inflammatory drugs only (7/36, 20%). Twenty patients (56%) experienced other irAEs, with rheumatic and dermatological being the most common. All three patients with high-grade ICI-aOA also had another irAE diagnosis at some point after ICI initiation. ICI-aOA should be recognized as an adverse event of ICI immunotherapy. Early referral to a rheumatologist can facilitate the distinction between ICI induced inflammatory arthritis from post-ICI mechanical arthropathy, the latter of which can be managed with local therapy that will not compromise ICI efficacy.

Autoimmune complications of immunotherapy: pathophysiology and management.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

Impact of COVID-19 on patients with rheumatic complications of cancer immunotherapy: results of a registry survey.

Immune checkpoint inhibitors (ICI) block negative regulatory molecules, such as CTLA-4, PD-1 and PD-L1, in order to mount an antitumor response. T cells are important for antiviral defense, but it is not known whether patients with cancer treated with ICI are more or less vulnerable to viral infections such as COVID-19. Furthermore, immunosuppressive treatment of immune-related adverse events (irAE) may also impact infection risk. Rheumatic irAEs are often persistent, and can require long-term treatment with immunosuppressive agents. The aim of this study was to determine the incidence of COVID-19 infection and assess changes in ICI and immunosuppressive medication use among patients enrolled in a prospective rheumatic irAE registry during the height of the COVID-19 pandemic. On April 16 2020, following the 'surge' of COVID-19 infections in the New York Tri-State area, we sent a 23-question survey to 88 living patients enrolled in a single institutional registry of patients with rheumatic irAE. Questions addressed current cancer and rheumatic irAE status, ICI and immunosuppressant medication use, history of COVID-19 symptoms and/or diagnosed infection. A follow-up survey was sent out 6 weeks later. Sixty-five (74%) patients completed the survey. Mean age was 63 years, 59% were female, 70% had received anti-PD-(L)1 monotherapy and 80% had had an irAE affecting their joints. Six patients (10%) had definite or probable COVID-19, but all recovered uneventfully, including two still on ICI and on low-to-moderate dose prednisone. Of the 25 on ICI within the last 6 months, seven (28%) had their ICI held due to the pandemic. In patients on immunosuppression for irAE, none had changes made to those medications as a result of the pandemic. The incidence of COVID-19 was no higher in patients still on ICI. Ten percent of rheumatic irAE patients developed COVID-19 during the NY Tri-state 'surge' of March-April 2020. Oncologists held ICI in a quarter of the patients still on them, particularly women, those on anti-PD-(L)1 monotherapy, and those who had had a good cancer response. The incidence of COVID-19 was no higher on patients still on ICI. None of the patients on disease-modifying antirheumatic drugs or biological immunosuppressive medications developed COVID-19.