Rheumatic Immune-related Adverse Events Research Articles

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.

Bibliometric analysis of rheumatic immune related adverse events associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) has emerged as a popular cancer treatment approach. However, non-specific activation of T cells by ICIs can lead to immune-related adverse events (irAEs), including specific rheumatic manifestations. The study aimed to explore the current trend of ICIs associated rheumatic irAEs and summarize the knowledge structure through bibliometric methods. The Web of Science Core Collection database (WoSCC) was selected for retrieving literature on ICIs associated rheumatic irAEs. To evaluate contributions from different countries/regions, institutions, journals, and authors, bibliometric analysis software, including VOSviewer and CiteSpace, as well as bibliometric online platforms, were utilized to construct and visualize bibliometric networks. Through the systematic review of this knowledge domain, future research directions were determined. In This study, a total of 803 publications on ICIs-associated rheumatic irAEs were included for analysis. The distribution of these publications revealed two distinct growth phases: a stable phase between 2007 to 2015 followed by rapid growth from 2016 to 2020. The United States emerged as the top contributor in terms of publications, citations, and h-index, with the majority of leading institutions and funding agencies located there. Apart from government funding, pharmaceutical companies such as Bristol Myers Squibb and Merck Company also play a significant role in drug development and research. Analysis of keywords and citation bursts indicated that the initial burst was related to "monoclonal antibody," "anti-CLTA4 antibody," and "melanoma". This was followed by a rise in interest related to "sarcoidosis," "safety," "inflammatory arthritis," and "preexisting autoimmune." This study summarized the global research trends concerning ICIs associated rheumatic irAEs. The findings can provide valuable insights into the current understanding of rheumatic irAEs, highlight the research trend and developments in the field. Future efforts should focus on developing classification criteria and guidelines, conducting prospective studies, investigating the mechanisms involved, and identifying biomarkers for prediction and monitoring of these events.

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events

BackgroundRheumatic immune-related adverse events (R-irAEs) occur in 5–15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer...

Calprotectin in Patients with Rheumatic Immunomediated Adverse Effects Induced by Checkpoints Inhibitors.

this is an exploratory study to evaluate calprotectin serum levels in patients with rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) treatment. this is a retrospective observational study including patients with irAEs rheumatic syndromes. We compared the calprotectin levels to those in a control group of patients with RA and with a control group of healthy individuals. Additionally, we included a control group of patients treated with ICI but without irAEs to check calprotectin levels. We also analysed the performance of calprotectin for the identification of active rheumatic disease using receiver operating characteristic curves (ROC). 18 patients with rheumatic irAEs were compared to a control group of 128 RA patients and another group of 29 healthy donors. The mean calprotectin level in the irAE group was 5.15 μg/mL, which was higher than the levels in both the RA group (3.19 μg/mL) and the healthy group (3.81 μg/mL) (cut-off 2 μg/mL). Additionally, 8 oncology patients without irAEs were included. In this group, calprotectin levels were similar to those of the healthy controls. In patients with active inflammation, the calprotectin levels in the irAE group were significantly higher (8.43 μg/mL) compared to the RA group (3.94 μg/mL). ROC curve analysis showed that calprotectin had a very good discriminatory capacity to identify inflammatory activity in patients with rheumatic irAEs (AUC of 0.864). the results suggest that calprotectin may serve as a marker of inflammatory activity in patients with rheumatic irAEs induced by treatment with ICIs.

Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T-cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.

Rheumatic Diseases Development in Patients Treated by Anti-PD1 Immune Checkpoint Inhibitors: A Single-Centre Descriptive Study.

The introduction of the so-called immune checkpoint inhibitors (ICIs) substantially changed the history of cancer therapy. On the other hand, they can induce the development of rheumatic immune-related adverse events (Rh-irAEs). In the scenario of a joint oncology/rheumatology outpatient clinic, we conducted a single-centre descriptive study to define from a laboratory, clinical and therapeutic point of view, rheumatic conditions developed during anti-PD1 treatment. The study included 32 patients (M/F 16/16, median age 69, IQR 16.5). According to the international classification criteria, eight patients could be classified as affected by Rheumatoid Arthritis, one by Psoriatic Arthritis, six by Polymyalgia Rheumatica, five by systemic connective tissue diseases (two systemic lupus erythematosus, two Sjögren's syndrome, one undifferentiated connective tissue disease). The remaining patients were diagnosed as having undifferentiated arthritis or inflammatory arthralgia. The median interval between ICIs starting and the onset of symptoms was 14 weeks (IQR 19.75). Moving to treatment, the longitudinal observation revealed that all RA, PsA and CTD patients required the introduction of treatment with DMARDs. In conclusion, the growing use of ICIs in a real-life setting confirmed the possible development of different rheumatological conditions, further emphasising the need for shared oncology/rheumatology management.

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease-like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed.

Rheumatoid Arthritis Symptoms Diagnosed by Rheumatic Immune-related Adverse Events Caused by Nivolumab in a Patient with Esophageal Cancer.

This report described the case of a 70-year-old man who developed polyarthralgia after nivolumab treatment for recurrent esophageal cancer. Arthritis developed after initiating nivolumab therapy, and the patient tested positive for rheumatoid factor and anti-citrullinated peptide antibodies. The hand and elbow joints were already deformed, suggesting that he had had rheumatoid arthritis for several years and that the symptoms had only become apparent after nivolumab administration. This patient had rheumatoid arthritis, which was diagnosed as a nivolumab-induced rheumatic immune-related adverse event (rh-irAEs). Arthralgia during nivolumab administration can occur in rh-irAE cases. Patients should be assessed for autoimmune diseases before initiating immune checkpoint inhibitors.

Association Between Rheumatic Autoantibodies and Immune-Related Adverse Events.

Side effects of immune checkpoint inhibitors (ICIs), called immune-related adverse events (irAEs), closely resemble primary autoimmune or rheumatic diseases. We aimed to understand the clinical utility of rheumatic autoantibodies (rhAbs) for diagnosing irAEs. Patients without pre-existing autoimmune disease (pAID) who had cancer treated with ICI(s) treatment from 1/1/2011 to 12/21/2020 and a rhAb checked were retrospectively identified. Logistic regression assessed associations between autoantibodies and irAEs, cancer outcome, and survival. Specificity, sensitivity, and positive/negative predictive values (PPV, NPV) were estimated for key rhAbs and ICI-arthritis. Kaplan-Meier analyzed objective response rate (ORR) and overall survival (OS). A total of 2662 patients were treated with≥1 ICIs. One hundred and thirty-five without pAID had ≥ 1 rhAb tested. Of which 70/135(52%) were female; median age at cancer diagnosis was 62 years with most common cancers: melanoma (23%) or non-small cell lung cancer (21%), 96/135 (75%) were anti-PD1/PDL1 treated. Eighty had a rhAb ordered before ICI, 96 after ICI, and 12 before and after. Eighty-two (61%) experienced an irAE, 33 (24%) with rheumatic-irAE. Pre-ICI RF showed significant association with rheumatic-irAEs (OR = 25, 95% CI, 1.52-410.86, P = .024). Pre- and post-ICI RF yielded high specificity for ICI-arthritis (93% and 78%), as did pre- and post-ICI CCP (100% and 91%). Pre-ICI RF carried 93% NPV and pre-ICI CCP had 89% PPV for ICI-arthritis. No variables were significantly correlated with ORR. Any-type irAE, rheumatic-irAE and ICI-arthritis were all associated with better OS (P = .000, P = .028, P = .019). Pre-ICI RF was associated with higher odds of rheumatic-irAEs. IrAEs had better OS; therefore, clinical contextualization for rhAbs is critical to prevent unnecessary withholding of lifesaving ICI for fear of irAEs.

Autoantibody positivity predicts severity of rheumatic immune-related adverse events to immune-checkpoint inhibitors

ObjectiveImmune-related adverse events (irAEs) due to immune checkpoint inhibitors are responsible for a considerable burden of morbidity and mortality. Predictors of severity of rheumatic irAEs have not been identified yet. The objective of this study was to test the hypothesis whether the presence of autoantibodies could be associated with a more severe and difficult-to-treat clinical phenotype of rheumatic irAEs. MethodsPatients referred to our centre due to the onset of rheumatic irAEs were prospectively recruited between June 2018 and December 2020. A pre-specified panel of autoantibodies was tested in each patient at baseline visit. All patients were started on glucocorticoids and then followed-up. Conventional or biologic immunosuppressants were started in case of steroid-refractory or relapsing disease. Logistic regression analysis was performed to evaluate the association between the baseline positivity of at least one autoantibody and the necessity of an add-on therapy. ResultsFourty-three patients with rheumatic irAEs were enrolled. Twenty-five (58%) patients had positivity of at least one of the tested autoantibodies. Twenty-two (51%) patients required the start of an additional immunosuppressant during follow-up. The only factor associated with the necessity of an add-on therapy was autoantibody positivity (OR=9.65, 95% CI:2.09–44.56; p-value 0.004). ConclusionsThe presence of autoantibodies in patients with cancer who develop rheumatic irAEs could predict their progression to difficult-to-treat clinical manifestations. This finding might prompt a future therapeutic approach based on a tailored and earlier immunosuppressive treatment in selected cases.

Rheumatic immune-and nonimmune-related adverse events in phase 3 clinical trials assessing PD-(L)1 checkpoint inhibitors for lung cancer: A systematic review and meta-analysis.

We aimed to analyze rheumatic immune-related (ir) and nonimmune-related adverse events (AEs) due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature. We performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1-ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed. Eighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72]. Among rheumatic non-irAEs, both overall and severe (grade≥3) back pain were significantly more frequent in ICIs versus controls, 2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively. The overall frequency of arthralgia was similar between ICIs and controls; by sensitivity analysis RCTs assessing ICIs in combination with chemotherapy showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI. Rheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with them regardless its severity, while arthralgia only when ICIs are added on conventional chemotherapy.

Autoantibody positivity predicts severity of ICI-associated rheumatic immune-related adverse events

Autoantibody positivity predicts severity of ICI-associated rheumatic immune-related adverse events

Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Immune-Related Adverse Events Induced by Checkpoint Inhibitors. A Multicenter Study.

ObjectivesTo describe different clinical patterns of rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI) and their rheumatic and oncologic outcomes.MethodsWe classified clinical syndromes according to five different categories: non-inflammatory arthralgias (NIA), rheumatoid arthritis (RA)-like, psoriatic arthritis (PsA)-like, polymyalgia rheumatica (PMR)-like, and a miscellaneous group of patients with other syndromes. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response, and outcome.ResultsWe included 73 patients (64% male) with a mean age of 66.1 ± 11.6 years. Main underlying diagnosis was lung carcinoma in 29 (39%) patients, melanoma in 20 (27%), and renal-urothelial cancer in 11 (15%). Main ICI included Pembrolizumab in 24 (32%), Nivolumab 17 (23%), and Atezolizumab 7 (9 %). Seventeen out of seventy-three patients had an underlying rheumatic disease before ICI treatment. Fourteen patients developed other irAEs before or simultaneously with rheumatic syndromes. Main rheumatic irAEs included: RA-like in 31 (42.4%), NIA in 19 (26.0%), PMR-like in 10 (13.7%), and PsA-like in 5 (6.8%), among others. Median time from ICI to irAEs was 5 months (IQR 3–9). Those patients who received combined therapy, had a trend for an earlier presentation than those who received monotherapy (4.3 months IQR 1.85–17 vs. 6 months IQR 3–9.25, p = NS). Mean follow-up time was 14.0 ± 10.8 (SD, months). At the last visit, 47 % were taking glucocorticoids and 11% DMARD therapy. At the last visit, 13 (17.8%) patients remained with persistent arthritis, 19 (26%) had intermittent flares, and 39 (53.4%) had a self-limited pattern. Only in 15.1% of patients ICI therapy was discontinued.ConclusionsWe described different patterns according to treatment and irAEs. Combined ICI therapy had an earlier onset of symptoms. Patients who presented as RA-like, had a higher risk of persistent arthritis. After a mean follow-up of more than 1 year, one-fifth of the patients remained with persistent arthritis and 11% required DMARD therapy.

Predictors of Rheumatic Immune-Related Adverse Events and De Novo Inflammatory Arthritis After Immune Checkpoint Inhibitor Treatment for Cancer.

To identify predictors of rheumatic immune-related adverse events (irAEs) following immune checkpoint inhibitor (ICI) treatment for cancer. We performed a case-control study to predict the occurrence of rheumatic irAEs in cancer patients who initiated ICI treatment at Mass General Brigham and the Dana-Farber Cancer Institute between 2011 and 2020. We screened for the presence of rheumatic irAEs by reviewing the medical records of patients evaluated by rheumatologists or those prescribed nonglucocorticoid immunomodulatory drugs after the time of ICI initiation (baseline). Review of medical records confirmed the presence of rheumatic irAEs and the indications necessitating immunomodulatory drug treatment. Controls were defined as patients who did not experience rheumatic irAEs, did not have preexisting rheumatic disease, did not have a clinical evaluation by a rheumatologist after ICI treatment, did not receive an immunomodulatory drug after ICI, did not receive systemic glucocorticoids after ICI, and survived at least 6 months after the initial ICI treatment. We used logistic regression to estimate the odds ratios (ORs) (with 95% confidence intervals [95% CIs]) for the risk of a rheumatic irAE in the presence of various baseline predictors. A total of 8,028 ICI recipients were identified (mean age 65.5 years, 43.1% female, 31.8% with lung cancer). After ICI initiation, 404 patients (5.0%) were evaluated by rheumatologists, and 475 patients (5.9%) received an immunomodulatory drug to treat any irAEs. There were 226 confirmed rheumatic irAE cases (2.8%) and 118 de novo inflammatory arthritis cases (1.5%). Rheumatic diseases (either preexisting rheumatic diseases or rheumatic irAEs) were a common indication for immunomodulatory drug use (27.9%). Baseline predictors of rheumatic irAEs included melanoma (multivariable OR 4.06 [95% CI 2.54-6.51]) and genitourinary (GU) cancer (OR 2.22 [95% CI 1.39-3.54]), both relative to patients with lung cancer; combination ICI treatment (OR 2.35 [95% CI 1.48-3.74]), relative to patients receiving programmed death 1 inhibitor monotherapy; autoimmune disease (OR 2.04 [95% CI 1.45-2.85]) and recent glucocorticoid use (OR 2.13 [95% CI 1.51-2.98]), relative to patients not receiving a glucocorticoid, compared to the 2,312 controls without rheumatic irAEs. Predictors of de novo inflammatory arthritis were similar to those of rheumatic irAEs. We identified novel predictors of rheumatic irAE development in cancer patients, including baseline presence of melanoma, baseline presence of GU tract cancer, preexisting autoimmune disease, receiving or having received combination ICI treatment, and receiving or having received glucocorticoids. The proportion of cancer patients experiencing rheumatic irAEs may be even higher than was reported in the present study, since we used stringent criteria to identify cases of rheumatic irAEs. Our findings could be used to identify cancer patients at risk of developing rheumatic irAEs and de novo inflammatory arthritis and may help further elucidate the pathogenesis of rheumatic irAEs in patients with cancer who are receiving ICI treatment.

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

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.

Expert Perspective: Immune Checkpoint Inhibitors and Rheumatologic Complications.

Rheumatologists increasingly receive consults for patients treated with immune checkpoint inhibitors (ICIs) for cancer. ICIs can cause inflammatory syndromes known as immune-related adverse events (IRAEs). Several rheumatic IRAEs have been reported, including inflammatory arthritis, polymyalgia rheumatica, and myositis. For patients who present with musculoskeletal symptoms while receiving ICI therapy, it is important to have an algorithm for evaluation. The differential diagnosis includes a range of musculoskeletal syndromes, such as crystalline arthritis, mechanical issues, and osteoarthritis, in addition to IRAEs. After diagnosing a rheumatic IRAE, rheumatologists must work with the patient and the oncologist to form a treatment plan. Treatment of IRAEs is guided by severity. Evidence for management is limited to observational studies. Inflammatory arthritis and polymyalgia rheumatica are treated with nonsteroidal antiinflammatory drugs in mild cases, glucocorticoids for moderate-to-severe cases, and sometimes require other disease-modifying antirheumatic drugs. Myositis due to ICIs can be accompanied by myocarditis or myasthenia gravis. Glucocorticoids and withholding the ICI are usually required to treat myositis; some patients with severe myositis require intravenous immunoglobulin or plasmapheresis. Further research is needed to optimize treatment of IRAEs that does not compromise the antitumor effect of ICIs.

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

Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). 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. 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. 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.

Prevalence, therapy and tumour response in patients with rheumatic immune-related adverse events following immune checkpoint inhibitor therapy: a single-centre analysis.

Background:Immune checkpoint inhibitors (ICIs) improved cancer therapy by inducing a higher immune system activity. This effect can cause rheumatic immune-related adverse events (rh-irAEs), which have not yet been extensively studied.Methods:We analysed 437 patients between 2014 and 2019, treated with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1) at the Clinic for Internal Medicine III, Oncology, Haematology and Rheumatology at the University Hospital Bonn, Germany.Results:Of the 437 patients 60% were males. Patients were mainly treated for melanoma, lung cancer, head and neck tumour and urothelial carcinoma. At least one immune-related adverse event (irAE) was observed in 163 patients (37.3%), including rh-irAE. Most common side effects were rash, colitis and hepatitis. We identified 19 patients (4.3%) with a minimum of one rh-irAE due to ICI therapy; three of those had a pre-existing rheumatic disease. Arthralgia developed most frequently in eight patients (42.1%). Other rh-irAEs were: arthritis (n = 7; distinguished in rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and undifferentiated arthritis), myalgia (n = 2) and myositis (n = 3). Most rh-irAEs were classified as moderately severe (Common Terminology Criteria of Adverse Events grade 2: 68.4%). Median time between starting ICI therapy and the occurrence of rh-irAE was 109 days (interquartile range 40–420 days). Fifteen patients (78.9%) were treated with glucocorticosteroids. In four cases additional therapy with methotrexate or tocilizumab was required. Even though patients benefited from ICI treatment, therapy had to be discontinued in six of the participants due to rh-irAE. Interestingly, patients with rh-irAE had a significantly higher tumour response compared with patients without rh-irAE (94.4% versus 43.5%; p < 0.0001).Conclusion:Rh-irAEs occur under ICI therapy, especially in patients with higher tumour response. However, they are not the most frequent irAE after ICI exposure: 9.3% of all irAEs were rheumatic (20 rh-irAE cases in 19 patients of a total of 215 irAE cases in 163 patients).

Rheumatic immune-related adverse events associated with immune checkpoint inhibitors compared with placebo in oncologic patients: a systemic review and meta-analysis.

Objective:We aim to characterize the incidence and relative risk of rheumatic and systemic immune-related adverse effects (irAEs) among immune checkpoint inhibitor (ICI) therapy compared with those after placebo treatment.Methods:Randomized clinical trial studies with placebo control with the following keywords were searched from Embase, PubMed, Cochrane databases: immune checkpoint inhibitors, neoplasms, randomized controlled trials, and adverse effects.Results:Among the 5444 published and 316 registration records, nine placebo-controlled randomized clinical trials met our selection criteria, and included data from 5560 patients. Compared with placebo use, using ICIs increases the risk of overall-rheumatic irAEs. The incidence and relative risk of all-grade rheumatic irAEs were 18.40% [95% confidence interval (CI) 12.16–25.59%, p < 0.01] and 2.30 (95% CI 1.32–4.02), respectively, while musculoskeletal irAEs were 11.30% (95% CI 9.76–12.85%) and 1.01 (95% CI 0.84–1.22). The incidence and relative risk of severe rheumatic irAEs were 5.72% (95% CI 3.92–7.82%), and 8.29 (95% CI 3.75–18.35), respectively. Arthralgia was the most common rheumatic irAE (incidence 11.00%, 95% CI 9.55–12.64%; relative risk 0.99, 95% CI 0.82–1.19), although usually not severe. Colitis (incidence 3.23%, 95% CI 1.27–7.98%; relative risk 6.53, 95% CI 2.66–16.04) and pneumonitis (incidence 3.11%, 95% CI 1.56–6.21; relative risk 4.04, 95% CI 1.65–9.89) were commonly observed and tended to be severe. Hepatitis, hypophysitis, thyroiditis, and myositis were rare and less recorded, yet can be severe and life threatening. Other extremely rare severe rheumatic irAEs included sarcoidosis (n = 11), autoimmune arthritis (n = 8), autoimmune uveitis (n = 3), autoimmune pericarditis, bursitis, osteochondrosis, psoriasis, polymyalgia rheumatica, systemic inflammatory response syndrome, and Sjögren syndrome (n = 1, each).Conclusion:ICI therapy increased the incidence and relative risk of all-grade and severe rheumatic irAEs. Arthralgia was the most commonly observed non-severe irAE, while colitis and pneumonitis were commonly observed severe irAEs. Rare rheumatic irAEs like hepatitis, hypophysitis, thyroiditis, and myositis warrant special attention.

1809O TRheuMa registry provides real world data on rheumatic immune-related adverse events

1809O TRheuMa registry provides real world data on rheumatic immune-related adverse events