ORIGINAL RESEARCH published: 15 June 2022 doi: 10.3389/fmed.2022.888377 Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Edited by: Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Mariano Andres, Miguel Hernández University of Elche, Spain Reviewed by: Paola Savoia, A Multicenter Study Università degli Studi del Piemonte Orientale, Italy José A. Gómez-Puerta 1,2*† , David Lobo-Prat 3† , Carolina Perez-García 4† , Andrés Ponce 1† , Zulema Rosales Rosado, Beatriz Frade-Sosa 1† , Ana Milena Millán Arciniegas 3 , Fabiola Ojeda 4† , Hospital Clínico San Carlos, Spain Virginia Ruiz-Esquide 1† and Hector Corominas 3† on Behalf of CAPICAT-MAS ‡ Nicolai Leuchten, 1 Rheumatology Department, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, University Hospital Carl Gustav Spain, 2 Department of Medicine, Universitat de Barcelona, Barcelona, Spain, 3 Rheumatology Department, Hospital de la Carus, Germany Santa Creu i Sant Pau, Barcelona, Spain, 4 Rheumatology Department, Hospital del Mar, Barcelona, Spain *Correspondence: José A. Gómez-Puerta jagomez@clinic.cat Objectives: To describe different clinical patterns of rheumatic immune-related adverse † ORCID: events (irAEs) induced by immune checkpoint inhibitors (ICI) and their rheumatic and José A. Gómez-Puerta oncologic outcomes. orcid.org/0000-0001-8177-702X David Lobo-Prat Methods: We classified clinical syndromes according to five different categories: orcid.org/0000-0002-4649-1904 Carolina Perez-García non-inflammatory arthralgias (NIA), rheumatoid arthritis (RA)-like, psoriatic arthritis (PsA)- orcid.org/0000-0002-6695-6406 like, polymyalgia rheumatica (PMR)-like, and a miscellaneous group of patients with other Andrés Ponce syndromes. We conducted a baseline visit and then follow-up in order to determine their orcid.org/0000-0003-3068-5752 Beatriz Frade-Sosa clinical pattern, treatment response, and outcome. orcid.org/0000-0002-5867-8434 Fabiola Ojeda Results: We included 73 patients (64% male) with a mean age of 66.1 ± orcid.org/0000-0002-6734-9288 11.6 years. Main underlying diagnosis was lung carcinoma in 29 (39%) patients, Virginia Ruiz-Esquide melanoma in 20 (27%), and renal-urothelial cancer in 11 (15%). Main ICI included orcid.org/0000-0002-2657-6601 Hector Corominas Pembrolizumab in 24 (32%), Nivolumab 17 (23%), and Atezolizumab 7 (9 %). orcid.org/0000-0002-7738-6787 Seventeen out of seventy-three patients had an underlying rheumatic disease before ‡ CAPICAT-MAS: Systemyc ICI treatment. Fourteen patients developed other irAEs before or simultaneously with Autoimmune Diseases and rheumatic syndromes. Main rheumatic irAEs included: RA-like in 31 (42.4%), NIA Capillaroscopy Study Group of Catalan Society of Rheumatology 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 Specialty section: This article was submitted to combined therapy, had a trend for an earlier presentation than those who received Rheumatology, monotherapy (4.3 months IQR 1.85–17 vs. 6 months IQR 3–9.25, p = NS). Mean a section of the journal Frontiers in Medicine follow-up time was 14.0 ± 10.8 (SD, months). At the last visit, 47 % were taking Received: 02 March 2022 glucocorticoids and 11% DMARD therapy. At the last visit, 13 (17.8%) patients Accepted: 12 May 2022 remained with persistent arthritis, 19 (26%) had intermittent flares, and 39 (53.4%) Published: 15 June 2022 had a self-limited pattern. Only in 15.1% of patients ICI therapy was discontinued. Frontiers in Medicine | www.frontiersin.org 1 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors Conclusions: We 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. Keywords: immunotherapy, adverse (side) effects, checkpoint, arthritis, polymyalgia rheumatica INTRODUCTION centers in Barcelona (Hospital Clinic, Hospital de la Santa Creu i Sant Pau, and Hospital del Mar) due to the onset The appearance of immune checkpoint inhibitors (ICI), of rheumatic syndromes related to ICI treatment. The study including anti- cytotoxic T lymphocyte antigen-4 (anti-CTLA-4), period included patients who visited from January 2015 to and programmed cell death-1 (PD-1)/programmed death-ligand January 2021. Data collected included demographic features, 1 (PD-L1) monoclonal antibodies, constitutes one of the major history of rheumatic diseases as well as ICI indication and type, medical breakthroughs in oncology treatment, leading to presence of non-rheumatic irAEs, disease manifestations at irAE impressive clinical results in different types of cancer (1). onset, and treatment. The diagnostic and treatment approach However, ICI might induce several side effects such as was done according to clinical judgment in the daily clinical immune-related adverse events (irAEs) that can add important practice setting. Any type of tumors or hematologic neoplasms morbidity and disability in oncologic patients. There is an were included. In order to avoid potential side effects due to increase in the number of reports of rheumatic irAEs, due to an chemotherapy (CT), patients who received combined therapy increased usage of ICI as well as a better recognition of these with CT plus ICI were excluded. new associations. Overall, they occurred in around 5–10% of We classified clinical syndromes according to 5 different patients receiving ICI according to some recent reports (2–5), but categories: (a) non-inflammatory arthralgia (NIA), (b) sometimes many symptoms such as arthralgias, myalgias, fatigue, rheumatoid arthritis (RA)-like, (c) psoriatic arthritis (PsA)- or sicca symptoms are underreported and/or misclassified in like in patients with oligo/polyarthritis with or without enthesitis randomized clinical trials as musculoskeletal disorders. The and tenosynovitis, (d) polymyalgia rheumatica (PMR)—like spectrum of irAEs includes a wide range of immune-mediated in patients with inflammatory proximal muscle pain with or syndromes. ICI not only can induce inflammatory arthritis but without arthritis, and (e) a miscellaneous group of patients also systemic syndromes such as vasculitis (6), sarcoidosis-like with other syndromes including sicca syndrome, sarcoidosis, (7), myositis with or without myocarditis (8) and less frequently cutaneous or systemic vasculitis, or others. described cases of systemic lupus erythematosus (9), fasciitis Since there are no well-established protocols for the treatment (10), systemic sclerosis (11), antiphospholipid syndrome (12), of irAE rheumatic syndromes, treatment decisions were based and dermatomyositis (13) among others. on oncologists’ and rheumatologists’ clinical judgment and Knowledge of different rheumatic irAEs induced by ICI following the current guidelines for the treatment of rheumatic has increased in recent years and general recommendations irAEs (14). for treatment and follow-up have been developed for several academic societies (14, 15), however clinical patterns, time to Statistical Analysis onset of different irAEs according to treatment and follow-up are Descriptive statistics were reported as the mean ± standard less well-known. deviation for normal continuous variables, median and We aimed to describe the main clinical patterns with emphasis interquartile range (IQR) for non-normal continuous variables, on articular involvement, as well as the clinical course and and frequency and proportions for categorical variables. In prognosis of a series of rheumatic irAEs from three University bivariate analyses, differences in demographics, type of neoplasia centers in Barcelona. and treatment with the presence of persistent arthritis as primary outcome were compared using chi square tests or Fisher’s exact MATERIALS AND METHODS tests for categorical variables and Mann-Whitney U-tests for ordinal or continuous variables. We conducted an observational study including all adult patients We analyzed differences according to the type of treatment referred to the Rheumatology Departments in three University and initiation of rheumatic irAEs, as well as differences in appearance according to different syndromes. Also, we analyzed Abbreviations: ANA, antinuclear antibody; Anti-CTLA-4, anti-cytotoxic T according to ICI monotherapy or combined treatment. Kaplan- lymphocyte antigen-4; CT, chemotherapy; DMARD, Disease-modifying anti- Meier time-to-event analysis was used to determine the risk for rheumatic drugs; ICI, Immune checkpoint inhibitors; irAEs, Immune-related persistent arthritis during the follow-up excluding patients with adverse events; IQR, Interquartile range; NIA, non-inflammatory arthralgia; PD-1, Programmed cell death-1; PD-L1, Programmed death-ligand 1; PMR, Polymyalgia previous rheumatic disease. rheumatic; PsA, Psoriatic arthritis; RA, Rheumatoid arthritis; SE, Shared epitope; The statistical analysis was made using SPSS software (IBM UA, undifferentiated arthritis. SPSS version 23.0, Inc., Chicago, IL, USA) and GraphPad Frontiers in Medicine | www.frontiersin.org 2 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors Prism version 7.0 (GraphPad Software, San Diego, CA, USA). TABLE 1 | General characteristics, type of cancer and ICI molecules. All patients gave written informed consent. The study was N = 73 (%) approved first by the Hospital Clinic Institutional Review Board (HCB/2021/0901) and therefore in the other two Gender (Male) 46 (64.4) Ethics Committee. Mean current age (years ± SD) 66.1 ± 11.6 Mean time from CPI initiation and irAE onset (months ± SD) 7.7 ± 7.9 RESULTS Type of cancer N (%) Lung 29 (39.7) A total of 73 patients were included. Most of the patients were Melanoma 20 (27.3) male (64%) and the mean age at the moment of inclusion was Renal-urothelial 11 (15.0) 66.1 ± 11.6 years. Main underlying diagnoses for ICI treatment Liver 2 (2.7) were lung carcinoma in 29 (39.7) cases, melanoma in 20 (27.3%), Breast 2 (2.7) renal-urothelial cancer in 11 (15%), liver carcinoma in 2 (2.7%), Acute myeloid leukemia 2 (2.7) breast cancer in 2 (2.7%), acute myeloid leukemia in 2 (2.7%), and Head and neck 2 (2.7) head and neck carcinoma in 2 (2.7%) among others. Ovarium 1 (1.3) Fifty five (75.0%) patients received another treatment for their Rectum 1 (1.3) oncologic diseases. A total of 34 (46.0%) received CT, 10 (13.0%) Thyroid 1 (1.3) radiotherapy and 9 (12.3%) surgery. Details for each patient are Skin 1 (1.3) collected in Supplementary Table 1. Myelodisplastic syndrome 1 (1.3) Only 16 (21.9%) out of 73 patients had any rheumatologic Previous rheumatic/inflammatory diseases disease before ICI, but only 9 had an underlying None 57 (78.1) inflammatory disorder including RA in 3 (4.1%) patients, Rheumatoid arthritis 3 (5.4) spondyloarthropathies in 2 (3.2%) patients and two patients with Gout 3 (4.1) PsA (3.2%) (Table 1), among others. Sixteen (21.9%) out of 73 Spondyloarthritis 2 (3.2) patients had 19 non-rheumatic irAEs before or simultaneously Chondrocalcinosis 2 (2.7) with the appearance of rheumatic syndrome, and three cases Psoriasis 2 (2.7) after rheumatic irAEs. Those non-rheumatic irAE syndromes Systemic lupus erythematosus 1 (1.4) included: colitis in 5 (8%), hypothyroidism in 3 (4.1%), and peripheral neuropathy in 2 (2.7%), among others (Table 2). Cryoglobulinemia 1 (1.4) Mean time from ICI initiation and non-rheumatic irAE was/ Fibromyalgia 1 (1.4) 7.65 ± 7.60 months. De Quervain tendinitis 1 (1.4) Type of Checkpoint inhibitors Clinical Presentation Monotherapy N = 60 (82.2) Most of the patients complained of articular or periarticular Pembrolizumab 24 (32.9) symptoms including generalized arthralgias in 25 (34.2%), Nivolumab 17 (23.3) polyarthritis in 12 (16.4%), proximal weakness, pain and stiffness Atezolizumab 7 (9.6) in the shoulders and hips in 11 (15.0%), monoarthritis in 9 Durvalumab 7 (9.6) (12.3%), oligoarthritis in 7 (9.5%), tenosynovitis in 4 (5.4%), Anti-TIM3 3 (4.1) paresthesias in 2 (2.7%), and purpura, symmetrical synovitis with Avelumab 1 (1.4) pitting edema, and subcutaneous nodules in one case each. Ipilimumab 1 (1.4) Finally patients were labeled according to clinical judgment Combined therapy N = 13 (17.8) with the following diagnosis: RA-like in 31 (42.4%), PMR in 10 Nivolumab + Ipilimumab 8 (11.0) (13.7%), PsA-like in 5 (6.8%), seronegative tenosynovitis in 3 Pembrolizumab + Epacadostat 2 (2.7) (4.1%), vasculitis in 2 (2.7%), gout in 2 (2.7%), and sarcoidosis Durvalumab + Tremelimumab 1 (1.4) in 1 (1.4%). Nineteen patients (26.0%) were classified as NIA. Pembrolizumab + Eftilagimod 1 (1.4) Median time from ICI treatment and irAE onset was 5 months Ibatasertib + Atezolizumab 1 (1.4) (IQR 3–9 months). Differences according to time of onset and Anti-TIM3, Anti T cell immunoglobulin mucin domain 3. rheumatic irAE are presented in Figure 1. We found some patterns of earlier presentation in those with vasculitis [median time 2 months (IQR 1.7–5.0)] and tenosynovitis [median time was observed in 5 out of 73 (6.8%) and anti-CCP in 4 out of 71 3.5 months (IQR 2.0–7.5)] while a later presentation was found (5.6%) patients. in those patients with RA-like [median time 6 months (IQR 3.0– Three cases of irAEs induced by Anti T cell immunoglobulin 11.0)], PsA-like [median time 7.5 months (IQR 1.7–26)], and mucin domain 3 (anti-TIM3) deserve special attention. Clinical PMR-like [median time 7 months (IQR 1–14)] patterns. characteristics of those patients are presented in Table 3 and Autoimmune assessment revealed positivity for antinuclear discussed later. antibody (ANA) (≥1/80) in 24 out of 72 (33%) patients, but Time (in months) from ICI initiation to irAE onset only in 6 (8.2%) cases was ANA > 1/320; rheumatoid factor was different according to treatments (Figure 2A). For Frontiers in Medicine | www.frontiersin.org 3 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors TABLE 2 | Main irAEs non rheumatic features. of 4.4 ± 7.5 mg per day, and disease-modifying anti-rheumatic drugs (DMARDs) in 8 (11.0%) patients (hydroxychloroquine Non-rheumatic irAEs N (%) in four, methotrexate in three, and sulfasalazine in one). Four None 57 (78.0) (5.5%) patients received intra-articular glucocorticoid treatment. Colitis 5 (6.8) In 59 (80.8%) patients, no discontinuation of ICI was needed, Hypothyroidism 5 (6.8) in 3 (4.1%) patients combined treatment was changed to Peripheral neuropathy 2 (2.7) monotherapy, and in 11 (15.1%) ICI therapy was discontinued. Hypophysitis 1 (1.3) Sarcoidosis 1 (1.3) Outcome and Follow-Up Mean time follow-up was 14.0 ± 10.8 (months). Two patients Sweet syndrome 1 (1.3) were lost to follow-up. At the last visit, 13 (17.8%) patients Vitiligo 1 (1.3) remained with persistent arthritis, 19 (26.0%) had intermittent Interstitial nephritis 1 (1.3%) flares, and 39 (53.4%) had a self-limited pattern. Persistent Pneumonitis 1 (1.3%) arthritis was statistically significantly more common in male than Hepatitis 1 (1.3%) female patients (69.2 vs. 30.8%, p = 0.018). Some patients presented more than 1 non-rheumatic irAE. Patients who had the RA-like pattern had a significantly higher In 3 patients, non-rheumatic irAE presented after rheumatic irAE. risk for persistent arthritis (Figure 3). No differences were found in the percentage of persistent arthritis in patients with or without previous rheumatic disease, neither with the type of cancer or type of ICI treatment (monotherapy or combined therapy). No differences in the proportion of patients in arthritis remission in patients with or without current glucocorticoid (GC) use were observed. Regarding oncologic outcomes, 20 (27.4%) patients were in remission, 24 (39.4%) in partial response, and 27 (37.0%) with tumor progression. Fifteen (20.5%) patients died. DISCUSSION We reported clinical patterns and follow-up of rheumatic irAEs from three referral centers. RA-like, PsA, PMR-like, and non- inflammatory complaints were the main clinical phenotype identified in our cohort. After at least 1 year of follow-up, more than half of patients had a self-limited flare, 26% had an intermittent course with flares and remission, and 18% had a chronic persistent pattern as occurs in inflammatory arthritis. Around 500 patients have been reported in different cohorts of patients mainly from the USA, Canada, France, and Spain (Supplementary Table 2) (2, 3, 5, 10, 16–20). According to previous published data, male patients were the majority (53%), FIGURE 1 | Time to onset from ICI initiation and Rheumatic irAEs according with a mean age of 62.8 ± 3.8 years, and 23% of patients were rheumatic diagnosis. under DMARD treatment. Information about predictors of rheumatic irAEs in patients exposed to ICI treatment without previous autoimmune diseases Pembrolizumab, 4 months (IQR 2–9), Nivolumab 6 months is limited. One study evaluated the presence of HLA class II (IQR 3–12.6), Atezolizumab 6 months (IQR 1–7.5), Durvalumab shared epitope (SE) alleles in 27 patients who developed irAEs 8 months (IQR 7–11), and anti-TIM3 9 months (IQR 2–11). and in 299 controls. 61.5% of patients with inflammatory arthritis Those patients who received combined therapy, had a trend induced by ICI had at least one SE allele vs. 41.2% of controls for an earlier presentation than those who received monotherapy (16). A very recent study (21) reported that those patients (4.3 months IQR 1.85–17 vs. 6 months IQR 3–9.25, p = NS with melanoma, genitourinary cancer, with pre-existing non- (Figure 2B). rheumatic autoimmune diseases and who received combination therapy were predictors for the development of rheumatic irAE. Treatment Kostine and colleagues described four different forms of Rheumatic syndromes were treated according to American presentation in a series of 35 patients with rheumatic irAEs Society of Clinical Oncology guidelines including NSAIDs in 23 from 524 patients treated with ICI in a single center (3). Those (31%) patients, glucocorticoids ever used in 44 (60.0%) patients, patterns included PMR, RA, PsA among inflammatory arthritis, and currently used in 35 (47.7%) patients with a mean dose and one group with non-inflammatory complaints. Interestingly Frontiers in Medicine | www.frontiersin.org 4 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors TABLE 3 | Clinical characteristics of patients treated with Anti-TIM3. Case Age/ Underlying disease Previous Rheumatic/ Other irAEs Presenting irAEs Rheumatic Gender immuno-mediated disease symptom syndrome 1 72/Male Acute myeloid leukemia Uveitis B27 positive None Knee monoarthritis UA 2 72/Male Acute myeloid leukemia Psoriasis Sweet syndrome Knee monoarthritis PsA 3 75/Male Myelodysplastic syndrome None None Tenosynovitis Tenosynovitis UA, Undifferentiated arthritis; PsA, Psoriatic arthritis; TIM3, T cell immunoglobulin and mucin domain 3. FIGURE 2 | Time to onset from ICI initiation and Rheumatic irAEs according treatment. (A) Type of treatment; (B) Monotherapy vs. combined. enough, patients who develop rheumatic irAEs had higher tumor described for inflammatory arthralgias by Buder- Bakhaya responses than those patients without irAEs suggesting irAEs are and colleagues (25). Additionally, in our cohort, patients who predictive of a positive anti-tumor response (22). received Pembrolizumab, Nivolumab, and Atezolizumab had an To the best of our knowledge, we described here for the earlier onset of rheumatic irAEs. This data should be considered first time three patients who developed rheumatic irAE after with caution given the small number of cases in some types of anti-TIM3 treatment. The immune checkpoint protein TIM3 treatments. In a John Hopkins cohort (26), among 30 patients is a negative regulator of antitumor immunity. TIM3 has a with rheumatic irAEs, inflammatory arthritis presented after a suppressing role of antitumor immunity upon interaction with median time of 5 months, but no information according to type different ligands such as Galectin 9 (Gal9) (23). Blockade of of treatment or type of rheumatic diagnosis is given. TIM3/Gal9 is a novel therapeutic approach for hematological We found that those patients who presented vasculitis and myeloid malignancies and solid tumors such as breast and pure tenosynovitis had an earlier time to onset than patients prostate cancer (24). with RA-like, PMR, PsA-like, or NIA. A recent review of Few studies have explored the timing of the appearance rheumatic irAEs collecting previous reported cases analyzed time of the different rheumatic syndromes and the differences to symptom onset after ICI initiation and described a similar according to the treatment used. It is well-known that irAEs pattern, except for earlier presentation in PsA-like cases (27). are more often seen in patients exposed to combination therapy The follow-up and clinical course of patients with (22). We observed that rheumatic irAEs appeared earlier in inflammatory arthritis induced by ICI are less well-known. patients with combined therapy, this phenomenon was also Almost one out of five patients in our cohort had a persistent Frontiers in Medicine | www.frontiersin.org 5 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors FIGURE 3 | Persistent arthritis in (A) patients with monotherapy vs. combined therapy and (B) patients presented as RA-Like pattern vs. other patterns. arthritis pattern, which has been more common in male patients Limitations of the current study include the retrospective and in patients with the RA-like pattern, excluding patients with nature of the analysis and selection bias of the study cohort previous rheumatic disease. CanRIO is a Canadian registry that since only symptomatic patients were referred to Rheumatology included adult oncologic patients treated with either CTLA-4, departments. Additionally, a standardized protocol was PD-1, or PD-L1 in 10 different centers. CanRIO reported new not followed as the study was conducted in real-world onset inflammatory arthritis in 45 patients, being persistent in practice. However, we also have strengths, including a 42.0% of them (26). In another cohort of 60 patients followed relatively big cohort of patients with a clinical follow-up during a median of 9 months, persistent arthritis was related for more than 1 year and the inclusion of new ICI such with combined ICI therapy, longer ICI exposure and prior as anti-TIM3. development of other irAEs (28). Several questions remain unanswered in the field of rheumatic Only 11.0% of our patients required DMARD treatment, irAEs including DMARD treatment duration, the impact of and none received biologic DMARDs. Treatment of rheumatic immunosuppressive drugs over oncologic prognosis, as well as irAE is a challenge for clinicians, including rheumatologists and the identification of more predictors for the development of irAE, oncologists. The balance between risk and benefits should be including rheumatic and non-rheumatic syndromes. individualized according to oncologic prognosis, ICI response, Rheumatic irAEs are still an open scenario and further and severity of the irAE (29). The clinical scenario differs studies will be needed including new ICI, new combinations from the “classic” pattern that we usually see in inflammatory of anti-CTLA-4 plus anti-PD1 or anti-PD-L1, and studies with chronic arthritis and systemic rheumatic diseases, and many longer follow-up. patients had a milder course with fewer requirements for GC or DMARDs (17). Myositis cases could be severe and might suggest a life-threatening situation and require intravenous pulses of DATA AVAILABILITY STATEMENT glucocorticoids and intravenous immunoglobulins among others The raw data supporting the conclusions of this article will (15). Some authors suggest a change in the paradigm for the be made available after request by the authors, without treatment of rheumatic irAEs, pivoting to a more aggressive undue reservation. approach with early use of biologic DMARDs similar to what occurs in patients with colitis induced by ICI (30). Experience with biologic DMARDs is limited, but some cases reported ETHICS STATEMENT satisfactory responses with IL-6 inhibitors or TNF-α inhibitors without a significant impact on tumor response (17, 18, 31, 32). The studies involving human participants were reviewed Around one fifth of our cohort had a previous rheumatic and approved by Hospital Clinic Institutional Review Board disease. We did not find higher rates of persistent arthritis (HCB/2021/0901). The patients/participants provided their in patients with previous rheumatic disease. In CanRIO (33) written informed consent to participate in this study. they reported irAEs in 27 patients with preexisting autoimmune disease mainly RA, psoriasis/PsA, and inflammatory bowel AUTHOR CONTRIBUTIONS disease among others. Around half of the patients developed flares of underlying disease, mostly mild, and one-third of the JG-P, HC, and CP-G had access to the study data, developed the patients had a severe flare that led to ICI discontinuation. figures and tables, wrote the first draft of the manuscript, and Frontiers in Medicine | www.frontiersin.org 6 June 2022 | Volume 9 | Article 888377 Gómez-Puerta et al. Rheumatic irAEs Induced by Checkpoint Inhibitors vouch for the data and analyses. AP, BF-S, JG-P, HC, CP-G, DL-P, for assisting in figure design. We also thank Shelby FO, AM, and VR-E contributed to study design, data collection, Marozoff and Antonio Aviña Zubieta for their review of and patient’s follow-up. the manuscript. ACKNOWLEDGMENTS SUPPLEMENTARY MATERIAL The authors would like to thank Sebastian Rodriguez García The Supplementary Material for this article can be found and Roberto Gumucio for assisting in data collection online at: https://www.frontiersin.org/articles/10.3389/fmed. in the initial phases of the project and Tomas Urrego 2022.888377/full#supplementary-material REFERENCES 15. Kostine M, Finckh A, Bingham CO, Visser K, Leipe J, Schulze- Koops H, et al. EULAR points to consider for the diagnosis and 1. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events management of rheumatic immune-related adverse events due to cancer associated with immune checkpoint blockade. New Eng J Med. (2018) immunotherapy with checkpoint inhibitors. Ann Rheum Dis. 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Rheumatic manifestations and diseases from immune checkpoint inhibitors in cancer Publisher’s Note: All claims expressed in this article are solely those of the authors immunotherapy. Front Med. (2021) 8:762247. doi: 10.3389/fmed.2021.76 and do not necessarily represent those of their affiliated organizations, or those of 2247 the publisher, the editors and the reviewers. Any product that may be evaluated in 30. van der Geest KSM, Sandovici M, Rutgers A, Hiltermann TJN, this article, or claim that may be made by its manufacturer, is not guaranteed or Oosting SF, Slart RHJA, et al. Management of immune checkpoint endorsed by the publisher. inhibitor-induced polymyalgia rheumatica. Ann Rheum Dis. (2020). doi: 10.1136/annrheumdis-2020-218276. [Epub ahead of print]. Citation: Gómez-Puerta JA, Lobo-Prat D, Perez-García C, Ponce A, Frade- 31. Stroud CR, Hegde A, Cherry C, Naqash AR, Sharma N, Addepalli S, Sosa B, Millán Arciniegas AM, Ojeda F, Ruiz-Esquide V and Corominas H (2022) et al. Tocilizumab for the management of immune mediated adverse Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Immune- events secondary to PD-1 blockade. J Oncol Pharm Pract. (2019) 25:551– Related Adverse Events Induced by Checkpoint Inhibitors. A Multicenter Study. 7. doi: 10.1177/1078155217745144 Front. Med. 9:888377. doi: 10.3389/fmed.2022.888377 32. Chatzidionysiou K, Liapi M, Tsakonas G, Gunnarsson I, Catrina A. Treatment of rheumatic immune-related adverse events due to cancer immunotherapy with immune checkpoint inhibitors—is it time for a paradigm shift? Copyright © 2022 Gómez-Puerta, Lobo-Prat, Perez-García, Ponce, Frade-sosa, Clin Rheumatol. (2021) 40:1687–95. doi: 10.1007/s10067-020-05 Millán Arciniegas, Ojeda, Ruiz-Esquide and Corominas. This is an open-access 420-w article distributed under the terms of the Creative Commons Attribution License (CC 33. Hoa S, Laaouad L, Roberts J, Ennis D, Ye C, Al Jumaily K, et al. Preexisting BY). The use, distribution or reproduction in other forums is permitted, provided autoimmune disease and immune-related adverse events associated with the original author(s) and the copyright owner(s) are credited and that the original anti-PD-1 cancer immunotherapy: a national case series from the Canadian publication in this journal is cited, in accordance with accepted academic practice. research group of rheumatology in immuno-oncology. Cancer Immunol No use, distribution or reproduction is permitted which does not comply with these Immunother. (2021) 70:2197–207. doi: 10.1007/s00262-021-02851-5 terms. Frontiers in Medicine | www.frontiersin.org 8 June 2022 | Volume 9 | Article 888377