Assessment of immune-related rheumatological adverse events in a monovalent oncology center in Argentina

Assessment of immune-related rheumatological adverse events in a monovalent oncology center in Argentina | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assessment of immune-related rheumatological adverse events in a monovalent oncology center in Argentina María Victoria Collado, María Natalia Gandur, Stella Maris Ranuncolo, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5005235/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors (ICIs) has changed the outcome of oncology patients. They are being used in an increasingly number of different cancer types. As a consequence, there is an enhance report of toxicity ICIs associated, named immune related adverse events. Herein we focused on the description of the Immune related Rheumatologic Adverse Events (IrRAEs) in oncological patients treated with ICIs, determining the continuity of the oncological treatment following their development, and investigating whether pre-existing rheumatologic disease (PRD) was the reason for not initiating the ICI treatment. Methods it is a descriptive and retrospective study. Included 42 oncology patients, initiating or already undergoing an ICI treatment, who were referred to the Rheumatology Department during 2019–2022. Results 40/159 (25%) patients that received ICI treatment at the Institute of Oncology “Ángel H. Roffo”, were evaluated by the Rheumatology Department. 16/40 experienced IrRAEs. Treatment of IrRAEs: 5/16 received non-steroidal anti-infammatory drugs, 11/16 corticosteroids (5/11 required additionally Disease-Modifying Antirheumatic Drugs (DMARDs). The IrRAEs treatment outcome was complete response (9/16), partial response (2/16) and no response (5/16). As a consequence 7/16 patients (44%) were able to continue the ICI therapy, 3/16 (19%) experienced a temporary suspension and 6/16 (37%) a permanent discontinuation. Two patients did not iniciate ICIs due to PRD. Conclusions 25% of the total ICI treated patients developed rheumatologyc symptoms. The IrRAEs were the cause of them in 16/40 patients. Therefore 10% (16/159) of the total ICI treated patients developed IrRAEs. Most of the IrRAEs observed were mild to moderate. Only one patient, who suffered myositis, experienced a severe life-threatening IrRAE. The patients´ evaluation at the time they started the ICI therapy allowed the diagnosis of PRD and to monitore exacerbations. More than half of the patients who developed IrRAEs were capable to continue their ICI treatment. Immune checkpoint inhibitors immune-mediated rheumatologic adverse events pre-existing rheumatologic disease oncological patients Background Immunotherapy drugs, named as Immune Checkpoint Inhibitors (ICI), play their role by blocking checkpoint proteins from binding with their corresponding partner proteins. This prevents the initiation of the “off” signal allowing T lymphocytes to identify malignant tumor cells. These include cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Immune checkpoints play a role in maintaining tolerance to self antigens in healthy individuals, preventing excessive activation of the immune system. However, the activation of the immune system can lead to the complication of loss of tolerance and the emergence of inflammatory or de novo autoimmune manifestations, or reactivation of pre-existing autoimmune diseases, known as immune-related adverse events (IrAEs) [ 1 ]. The IrAEs can affect any organ [ 2 ]. Its toxicity profile may vary depending on the type of ICI (for example, it has been reported that arthralgia and arthritis are more common in patients treated with PD-1/PD-L1 inhibitors than with anti-CTLA-4) [ 3 , 4 ] and also whether ICIs are given as monotherapy or as a combined therapy [ 5 ]. The IrAEs can appear while the patient is receiving the ICI treatment. They can also persist o start following their discontinuation (the latter being a common feature of the reumathologic manifestations) [ 6 ]. Depending on the IrAE severity, patients may require the ICI treatment suspension or evenmore an immunosuppressive therapy. There are still several answered questions, among others, the immune-related rheumatologic adverse events (IrRAEs) characteristics. According to reported data, the estimated prevalence of IrRAEs ranges from 1.5 to 22% [ 7 ]. It is suggested that there could be an underdiagnosis of this type of adverse events, which could be partially explained due to disparities in the definition of rheumatologic symptoms or their severity between oncology and rheumatology guidelines. Additionally, it should be considered the potencial benefit of a deeper exchange between the clinical oncology and rheumatology departments. Therefore, the primary objective of this study was to describe the characteristics of the IrAE with a rheumatologic nature in oncology patients undergoing ICI treatment, who were evaluated at the Rheumatology Department of the Angel H. Roffo Institute, an Argentinian monovalent oncology center. The secondary objectives were to assess the treatment and evolution of IrRAEs, as well as the continuity or discontinuation of oncologic treatment following their development. Additionally, the study aimed to describe cases where pre-existing rheumatologic diseases (PRD) were the reason for not initiating ICI treatment. Methods Patients The investigation has been conducted according to the principles expressed in the Helsinki Declaration and after the Ethics Committee on Research Protocols approval of the Institute of Oncology Ángel H. Roffo, School of Medicine, University of Buenos Aires. A descriptive and retrospective study was conducted at a monovalent Oncology hospital affiliated with the University of Buenos Aires, the Ángel H. Roffo Institute of Oncology. All patients aged ≥ 18 years, undergoing treatment or planning to initiate treatment with ICI, referred to the Rheumatology Department by the corresponding treating oncologist, were included. They were recruited during the period November 2019 and July 2022. The COVID19 pandemia had a significant impact on the recruitment. Patients included in the study were either initiating treatment or had received one or more doses of ICI (anti-CTLA-4: ipilimumab; anti-PD-1: nivolumab, pembrolizumab; anti-PD-L1: avelumab), either as a single drug or in combination according to oncologic indications approved by the National Administration of Drugs, Food, and Medical Technology of Argentina. For the analysis of the characteristics of IrRAEs, patients who did not initiate ICI treatment due to PRD, were excluded. The total number of ICI treatments performed at the Institute during the same time period of analysis of this study, was obtained from a retrospective analysis of the Day Hospital nursing records. The request for immunological laboratory tests was individualized based on the findings of the patient's interview and clinical evaluation. The study was approved by the Ethical Comittee of the Institute of Oncology “Ángel H. Roffo”. All patients included were informed regarding the study scope and objectives. Each one of them signed the corresponding informed consent. Statistical Analysis This is a descriptive, retrospective, observational study. Data was stored digitally using Microsoft Office® Excel. For descriptive statistics, Microsoft® Excel was employed. Continuous variables were described using either mean and standard deviation or median and range, depending on their distribution. Results From November 2019 to July 2022, 190 patients were evaluated in the Rheumatology Department, of which 42 patients (22%) met the inclusion criterias for this study: 7 were referred for evaluation before the initiation of the ICI therapy and 35 were referred for having developed rheumatologic symptoms after the initiation of the ICI treatment. During the same time frame, 159 patients underwent ICI treatment at our Institute according the retrospective analysis of the nursing records of the Day Hospital (Table 1). The median number of ICI treatments for the total treated patients was 3 (1-37). Table 1. Oncological patients evaluated by the rheumatological department. Descriptive table of the number of ICI treatments conducted at the Angel H. Roffo Oncology Institute from November 2019 to July 2022, based on the retrospective analysis of nursing records. The table includes the number of patients evaluated by the rheumatology department and the number of patients who developed immune-mediated rheumatological adverse events. Type of tumor Melanoma Renal Bladder Prostate H and N Lung Breast Cervix Lymphomas Colon Others Total Number of ICI treatments conducted at the Angel H. Roffo Oncology Institute 67 40 10 1 4 16 4 9 3 3 2 159 Number of patients with ICI therapy assessed in Rheumathology 13 15 8 0 0 1 0 1 1 1 0 40 Number of patients with IrRAE 7 4 2 0 0 0 0 1 1 1 0 16 References: ICI = immune checkpoint inhibitors, IrRAE = immune-related rheumatological adverse events, H and N = Head and Neck. Descriptive table of the number of ICI treatments conducted at the Angel H. Roffo Oncology Institute from November 2019 to July 2022, based on the retrospective analysis of nursing records. The table includes the number of patients evaluated by the rheumatology department and the number of patients who developed immune-mediated rheumatological adverse events. Among the group of 7 patients referred for evaluation before the initiation of the ICI therapy, 3/7 were diagnosed with PRD: Systemic sclerosis, gout and polymyalgia rheumatica (PMR). Only the patient with PMR was capable of starting the ICI treatment. The other 4/7 patients, evaluated before the initiation of ICI who also started ICI treatment, were diagnosed with osteoarthritis (n=1/4) and oncologic progression (n=3/4) as the cause of rheumatologic symptoms. Therefore, out of the 159 patients who received ICI treatment at the institute, 40 were evaluated in rheumatology (25%). Of the 40 patients who received ICI treatment, 25/40 (62%) were male. The mean age was 64 years (SD ± 11.54). The diagnosed cancer types were renal carcinoma (n=15/40), melanoma (n=13/40), bladder cancer (n=8/40), Hodgkin's lymphoma (n=1/40), lung cancer (n=1/40), colon carcinoma (n=1/40), and cervical cancer (n=1/40). Four patients (4/40) received a combination of anti-CTLA-4 and PD-1, and 36/40 were treated with single anti-PD-1 or single anti-PD-L1. The most frequently prescribed ICIs were Pembrolizumab (n=17) and Nivolumab (n=15). Twenty-five out of 40 patients received other oncologic treatments before the initiation of ICI therapy. The most common rheumatologic symptom that led patients to the Rheumatology Department was arthralgia (16/40 cases). Out of the 35/40 patients evaluated in the Rheumatology Department due to rheumatologic symptoms following the initiation of ICI treatment, in 16/35 cases the cause of those symptoms was an IrRAE. The diagnosed IrRAEs were: PMR (n=4/16), ICI-associated arthralgia (n=4/16), ICI-associated inflammatory arthritis (n=2/16), the SR3PE syndrome (remitting symmetrical seronegative synovitis with pitting edema) (n=2/16), myositis (n=1/16), and 3/16 cases were patients with PRD [2/3 Ankylosing Spondylitis (AS) and 1/3 Rheumatoid Arthritis (RA)] who expirienced an exacerbation of their previous disease. Nine out of the 16 patients with IrRAEs were male. The median number of ICI treatments received until the development of IrRAEs was 6 (2-30). All the patients had negative antibodies, except for patients with PRD and other two patients. One of these patient with knee arthritis had a positive antibody anti-cyclic ctrullinated peptide (ati-CCP). He developed a complete response to a moderate dose of corticosteroid and later negativized the anti-CCP. The other patient had arthralgia and elevated anti-nuclear antibody (ANA) with negative extractable nuclear antigens, anti-DNA, rheumatoid factor, and anti-CCP. He did not present synovitis or extra-articular manifestations and responded well to NSAID treatment. Seven of these patients had a first-degree relative with autoinmmune disease including rheumatoid arthritis (2), systemic erythematosus síndrome (1), ankylosing spondylitis (1), type I diabetes (1), vitiligo and type I diabetes (1) and hypothyiroidism (1). The remaining 19/35 patients presented as the cause of their consultation symptoms: non-rheumatologic irRAEs (n=3/19), Osteoarthritis (OA, n=6/19), oncologic progression (n=5/19), and in 5 cases: arthralgias (n=2/19), soft tissue rheumatism (n=2/19), and low back pain (n=1/19), whose association with ICI could not be definitely determined due to the lack of complementary studies needed for the establishment of that correlation. The patient diagnosed with PMR before the initiation of ICI did not experience an exacerbation of her disease during the ICI treatment. Seven out of the 16 patients with IrRAEs, also experienced non-rheumatologic IrAE (endocrinological, dermatological and gastrointestinal (Table 2). Out of the 16 patients with IrRAEs, 11 received corticosteroids with doses of meprednisone mild 30 mg/day (n=4/11). Five out of these patients (5/11), in addition to corticosteroids received as well conventional DMARDs: single Methotrexate or combination of Methotrexate and Hydroxicloroquine. Myositis was the most severe IrRAE. The patient required hospitalization, treatment with intravenous corticosteroids, Mycophenolate mofetil and anti-TNF (Infliximab). The patient died due to muscle weakness and respiratory failure. The other 5/16 patients only received treatment with NSAIDs. (Table 2). Therefore, out of the total patients with IrRAEs, 11/16 patients (69%) required corticosteroid treatment, of which 5/11 also required conventional DMARDs (31%). Regarding the response to this treatment: 6/11 had a complete response, two had a partial response (2/11) and 3/11 showed no response. Of the 5 patients who received conventional DMARDs, two required permanent discontinuations of ICI treatment, while the other 3 only required temporary suspension. Out of the 5/16 patients treated only with NSAIDs, 3/5 had a complete response, and 2/5 did not respond. On the other hand, it is important to emphasize that the 3/16 patients with PRD were able to continue with ICI treatment (Table 2). The follow-up of patients after IrRAEs treatment showed 7/16 patients (44%) were able to continue the ICIs therapy, 3/16 (19%) had to temporaly suspend it and 6/16 (37%) permanently discontinued it (Table 2). Among the 4 patients with a combination of anti-CTLA-4/PD-1, 2/4 (50%) experienced IrRAE (one PMR and other grade 2 arthalgia) and 2 had more severe non rheumatologic IrAEs (grade 4). In cases of rheumatologic manifestations not associated with ICI, the use of corticosteroids was not necessary. Table 2 Patients with immune-mediated rheumatological adverse events. Patient N Oncological Diagnosis ICI Rheumatological consultation Immunological laboratory Rheumatological diagnosis Non rheumatological IrAE IrRAE grade IrRAE treatment (corticosteoids maximal initial doses) IrRAE follow-up ICI Treatment decision following IrRAE 1 Melanoma N Hands arthritis Anti CCP- ANA- ENA- LA- ACL- normal C3 and C4 levels Arthritis 2 MPD 20 mg/day, Methotrexate 15 mg/week NR Temporary suspension 2 Melanoma N Weakness in the shoulder girdle and hands arthritis RF- anti CCP- ANA- ENA- ANCA- Polymyalgia rheumatica 2 MPD 40 mg/day, Methotrexate 15 mg/week NR Temporary suspension 3 Melanoma N Hands arthralgia ANA 1/1280 nuclear homogeneous ENA- anti dsDNA- RF- anti CCP- LA- Arthalgias 1 NSAI CR Permanent suspension 4 Melanoma I+N Weakness in both shoulder girdles RF- anti CCP- ANA- Polymyalgia Rheumatica Transaminitis Hypothyroidism 2 MPD 12 mg/day PR Continued treatment 5 Melanoma P Weakness in both shoulder girdles. RF- anti CCP- ANA- ENA- Polymyalgia Rheumatica Vitiligo 2 MPD 20 mg/day, Methotrexate 15 mg/week PR Permanent suspension 6 Melanoma N Hands arthralgia RF- anti CCP- Arthalgias 1 Paracetamol 1 g/day, NSAI NR Continued treatment 7 Melanoma P Weakness in both shoulder girdles RF- ANA- Polymyalgia Rheumatica Vitiligo hipothyroidysm Adrenal insufficiency 2 MPD 10 mg/day CR Temporary suspension 8 Renal P Hands edema with godet and arthritis RF- Anti CCP- ANA- Anti-SS-A/Ro- Anti-SS-B/La- SR3PE Syndrome 2 MPD 16 mg/day CR Permanent suspension 9 Renal P Hands arthritis Anti CCP+ RF- ANA- Anti-SS-A/Ro- Anti-SS-B/La- Pre-existing rheumatological disease exacerbation Dyarrhea 2 Methotrexate 7,5 mg/week HCQ 400 mg/day, MPD 4 mg/day. CR Temporary suspension 10 Renal N Achilles enthesitis and sacroiliitis HLA B27+ Pre-existing rheumatological disease exacerbation 2 NSAI CR Continued treatment. 11 Prostate and renal N Hands edema with godet and arthritis RF- Anti CCP- RS3PE Syndrome Transaminitis 2 MPD 4 mg/day CR Continued treatment 12 Bladder P Knees arthritis Anti CCP+ (later –) RF- ANA- ENA- normal C3 and C4 levels ANCA - Arthritis Pharmacodermy 2 Bethametasone, later MPD 8 mg/day CR Permanent suspension 13 Bladder N Inflammatory low back pain HLA B27+ Pre-existing rheumatological disease (AS) exacerbation Hypophysitis 2 NSAI DXM 8 mg/día CR Continued treatment 14 Hodgkin Lymphoma N Muscle weakness, dysnea, hands arthralgia, chest pain Can´t do it Myositis, miocarditis, pneumonitis 5 DXM 8 mg/day MMF, Infliximab 5 mg/Kg Death Death 15 Cervix P Hands and knees arthalgias RF- Anti CCP- ANA- ENA- Arthralgias 2 Pregabalin 150 mg/day NSAI D vitamin 100000 IU/month NR Continued treatment 16 Colon P Hands and knees arthalgias RF- Anti CCP-ANA- ENA- Arthralgias 2 Pregabalin 75 mg/day NSAI opioid pain reliever 50 mg/day. CR Continued treatment. Description of the 16 cases of immune-related rheumatological adverse events (IrRAEs). References: ACL= anti cardiolipin antibodies, ANA = antinuclear antibody, ANCA= antineutrophil cytoplasmic antibody, AR= rheumatoid arthritis, AS= ankylosing spondylitis, CCP= anti cyclic citullinated peptide, C3= complement factor 3, C4 = complement factor 4, CR = complete response, anti dsDNA= double stranded DNA antibody, DXM= dexamethasone, ENA= anti-extractable nuclear antigen antibodies, HCQ= hydroxychloroquine, HLA B27 = B*27 Human Leucocyte Antigen, ICI = Immune checkpoint inhibitor, IM = intramuscular, I= Ipilimumab, IrRAE = immune-related rheumatological adverse event, IU = International Units, LA= lupus anticoagulant, anti-La antibody = anti SS-B/La, MPD = meprednisone, mg = milligram, MMF= mycophenolate mofetil, N = Nivolumab, NSAI = Non-steroidal anti-inflammatories, NR = non response, PR = partial response, P= Pembrolizumab, RF= rheumatoid factor, anti Ro antibody = anti SS-A/Ro, RS3PE= remitting seronegative symmetrical synovitis with pitting edema syndrome. Discussion This study reports the frequency and characteristics of irRAE from a monovalent oncology center in Argentina, aiming to contribute data to enhance knowledge in an area where there is a scarcity of such information. Twenty five percent (40/159) of the total ICI treated patients in the Institute of Oncology Ángel H. Roffo were refered to the Rheumatologic Departure because of rheumatologyc symptoms development. The irRAEs were the cause of these symptoms in 40% (16/40) of the patients. When considering the total number of patients treated with ICI at our institute, it is observed that 10% (16/159) of them experienced IrRAEs, nevertheless it is not a prospective study, so not all patient were referred to the Rheumatology Department. In this regard, it might be considered that the treating oncologist requested rheumatology evaluations for cases with more severe symptoms or a history of rheumatologic disease. However, the percentage of patients referred to the Rheumatology Department is similar to that reported by Kostine et al., who prospectively studied 524 patients receiving ICI treatment, with 35 being refered to rheumatology due to IrRAEs (prevalence 6.6%) [8]. On the other hand, in 40% (16/40) of the patients referred to the rheumatology department who received ICI treatment, IrRAEs were confirmed. This implies that oncologists also referred mild severe non-inflammatory rheumatologic manifestations or cases mimicking rheumatologic diseases that required the rheumatologist evaluation for differential diagnosis. This aligns with findings reported by Mooradian MJ et al., who assessed 29 oncology patients from a single center, where 18 presented with IrRAEs, and 11 had another cause for musculoskeletal symptoms [9]. Therefore, it would be expected that collaboration as teamwork between rheumatologists and oncologists is promoted, there will be an improvement in the IrRAEs report and the patients monitoring. The most frequently detected IrRAEs in this study were ICI-associated arthralgia, ICI-associated arthritis (6/16 = 37.5%) and PMR (4/16 = 25%), consistent with the literature [1, 7, 10]. However, two cases of SR3PE were also identified, which has been less frequently reported in the literature [11, 12]. And three cases of exacerbations of PRD, which in general, are excluded from clinical studies. In two of these cases, the PRD was unknown to the patient and was identified during the rheumatological evaluation before the initiation of the ICI treatment. In three patients with PRD, an exacerbation of the preexisting disease was observed; nevertheless, all of them were able to continue the ICI treatment. It has been reported that patients with PRD, when treated with ICI, are more prone to develop IrRAEs, as exemplified by the study of Abdel-Wahab et al. This work reported the evaluation of 123 patients with cancer and PRD at the start of ICI treatment. It was observed that 75% of the analyzed patients had IrRAEs (41% an exacerbation of the underlying disease, 25% de novo IrRAE, and 9% both) [13]. This suggests that it would be advisable to have a prior assessment and multidisciplinary collaboration with a rheumatologist for the detection of PRD or follow-up in case of PRD because more than half of the cases may experience an exacerbation of the PRD. Despite this, with the proper control, it does not imply a contraindication to initiate the ICI treatment [1, 13-14]. The 56.25% of IrRAEs in this study occurred in men. Angelopoulou et al. evaluated 13 retrospective studies, reporting a total of 258 ICI-treated patients who developed IrRAEs, of which 154 were men (59.68%), suggesting that these manifestations appear to be more common in men than in women [1]. On the other hand, Triggianese et al. conducted a systematic review to assess the gender impact on IrRAEs by ICI and reported that Sicca/Sjögren's syndrome was observed in 50% of men compared to the primary disease, which affects only 5% of men [15]. More studies are needed to determine if this could be a difference between primary rheumatologic disease and IrRAE and to what extent other factors such as tumor histology or the type of ICI prescribed influence this phenomenon. Although most IrRAEs were of mild to moderate severity, in the case of a diagnosis of myositis, the patient passed away due to progression of muscular weakness and respiratory failure despite immunosuppressive treatment and discontinuation of ICI. The reported incidence of myositis is low (1-6%) [16], but it is known to involve greater severity, especially in cases of triple M syndrome: myositis, myocarditis, and myasthenia gravis. It requires aggressive immunosuppressive treatment and often needs permanent discontinuation of ICI [17]. If PRD is excluded, most of de novo IrRAEs (10/12) (83%) were seronegative. In accordance with this finding, it is known that antibodies are usually absent, in the de novo IrRAEs [8, 18. 19]. Angelopoulou et al. reported seropositivity in only 18.48% of the 211 patients tested in 15 evaluated retrospective studies. This seems to be another characteristic of IrRAEs compared to primary rheumatologic diseases. It could be speculated that there is a T CD8+ cell predominat activity in IrRAEs. Furthermore novel IrRAEs antibodies should be teasted beyond the ones currently available in daily practice as it being done in some studies [20, 21]. The combinated anti-CTLA-4 and anti-PD-1 treatment showed a higher risk of IrRAEs and greater severity of them than monovalent treatments. In the systematic review by Arnaud-Coffin P et al., which included 16,485 patients, they determined grade 3 IrRAEs in 14% of patients treated with anti-PD (L)-1, 34% in those treated with anti-CTLA-4, and 55% in those receiving combined treatment. In addition to the higher frequency, they also reported a higher grade of severity (> 3) of IrRAEs in patients under combined treatment [22]. Regarding the type of treatment, distinguishing IrRAEs from rheumatologic manifestations not associated with ICI limited the use of corticosteroids to cases of IrRAEs. Treatment with conventional DMARDs for IrRAEs or PRD helped improve symptoms control and allowed the continuation of ICI treatment in the majority of cases. In this study, 69% of patients received corticosteroid treatment, and 31% additionally required treatment with DMARDs, as reported in the literature. In this regard Angekopoulou F et al. evaluated 256 patients with musculoskeletal IrRAEs, with 70.52% and 18.45% requiring the above mentioned treatments respectively [1]. In our study, the most commonly used DMARD was methotrexate, and in the case of myositis, high-dose corticosteroid treatment, immunosuppressive therapy, and a biological DMARD were prescribed based on the severity of the condition. Leipe et al. reported in their study that methotrexate is a safe and effective drug as a corticosteroid-sparing agent in the treatment of ICI-induced arthritis [23, 24]. In rheumatology, the use of lower doses of corticosteroids and the use of DMARDs allowes to minimizing long-term damage and increasing patient survival [25]. Given that the survival of cancer patients is becoming increasingly prolonged due to new therapies, the increased reporting of IrRAEs will allow us to select the best treatments for them. This consideration should not only focus on immediate outcomes but also consider the long-term consequences of such treatments. Additionally, strategies for preventing IrRAEs in the case of PRD can be planned, as described in the report by Haanen J and col [1, 26]. The 63% of patients were able to continue the ICI treatment, indicating that in most cases, IrRAEs could be managed. This observation is in accordance with findings reported in the literature [1, 8-9]. We can consider as limitations of the current study the retrospective evaluation and a potential selection bias due to the non-systematic rheumatological assessment of the oncological patients who received ICI therapy. Conclusion In conclusion, we observed that 1 in 4 patients exposed to ICI in our institute presented rheumatologic symptoms requiring referral to the rheumatology department. IrRAEs was diagnosed in 1 of 10 of these cases after rheumatologist evaluation, emphasizing the importance of multidisciplinary collaboration. While most of these IrRAEs are of mild to moderate severity, in some cases, they can be severe and even life-threatening. Combined treatment with anti-CTLA-4 and anti-PD-1 posed a higher risk of IrAEs and increased risk of more severe IrAE. Rheumatological assessment prior to ICI initiation treatment contributed to identifying previously unknown pre-existing rheumatic conditions. The combinated follow-up by rheumatologists and oncologists facilitated the treatment of exacerbations in pre-existing rheumatic conditions and de novo IrRAEs, attempting to allow concurrent ICI treatment whenever possible. Distinguishing between IrRAEs and rheumatological manifestations not associated with ICI therapy alowed to restrict the use of corticosteroids to the IrRAEs cases. The addition of conventional DMARDs to IrRAEs treatment contributed to symptoms control and to continue the ICI treatment in the majority of the cases. Following the IrAEs treatment guidelines is essential, however, as reported cases increase, so does knowledge about various therapeutic opportunities with concomitant oncological and rheumatological treatments. Abbreviations ACL= anti cardiolipin antibodies ANA = antinuclear antibody ANCA= antineutrophil cytoplasmic antibody AR= rheumatoid arthritis AS= ankylosing spondylitis CCP= anti cyclic citullinated peptide C3= complement factor 3 C4 = complement factor 4 CR = complete response CTLA-4 = cytotoxic T-lymphocyte antigen 4 anti dsDNA= double stranded DNA antibody DXM= dexamethasone DMARDs = Disease-Modifying Antirheumatic Drugs ENA= anti-extractable nuclear antigen antibodies HCQ= hydroxychloroquine HLA B27 = B*27 Human Leucocyte Antigen ICI = Immune checkpoint inhibitor, IM = intramuscular, I= Ipilimumab, IrRAE = immune-related rheumatological adverse event, IU = International Units, LA= lupus anticoagulant, anti-La antibody = anti SS-B/La, MPD = meprednisone, mg = milligram, MMF= mycophenolate mofetil, N = Nivolumab, NSAI = Non-steroidal anti-inflammatories, NR = non response OA= Osteoarthritis P= Pembrolizumab PR = partial response PRD = pre-existing rheumatologic disease PD-1=programmed cell death-1 PD-L1=programmed cell death ligand-1 RF= rheumatoid factor anti Ro antibody = anti SS-A/Ro RS3PE= remitting seronegative symmetrical synovitis with pitting edema syndrome Declarations DeclarationsEthics approval: This research was approved by the Ethics Committee on Research Protocols of the Institute of Oncology “Ángel H. Roffo”, School of Medicine of the University of Buenos Aires. Consent to participate: Each one of the patients signed the corresponding informed consent. Consent for publication: Not applicable. Availability of data and material: data generated or analyzed during this study are available from the corresponding author on reasonable request. Declaration of competitive interests: MVC, MNG, SMR, SC, MC, VC, VC, MS, ICP, GC and MEZ declare that they have no conflict of interests. Funding: None to declare. Credit authorship contribution statement: MVC performed research, analyzed data and wrote the manuscript; MNG discussed pàtients´outcome; SMR wrote the manuscript; SC, MC, VC, VC, MS, ICP, GC, MEZ discussed patients´outcome. References Angelopoulou F, Bogdanos D, Dimitroulas T, Sakkas L, Daussis D. Immune checkpoint inhibitor‑induced musculoskeletal manifestations. Rheumatology International. 2020; 41: 33-42. Postow MA, Sidlow R, Hellmann MD. 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Kostine M, Finckh A, Bingham CO, Visser K, Leipe J, Schulze-Koops H et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann Rheum Dis. 2021; 80:36–48. Kostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriax C et al. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer—clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis. 2017; 77(3):393-398. Mooradian MJ, Nasrallah M, Gainor JF, Reynolds KL, Cohen JV, Lawrence DP et al. Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience. Semin Arthritis Rheum. 2019; 48(6):1127-1132. Capelli LC, Shah AA, Bingham 3 rd CO. Immune-related adverse effects of cáncer immunotherapy-implications for rheumatology. Rheum Dis Clin North Am. 2017; 43: 65-78. Yoshimura A, Yamanaka K, Tadokoro R, Wakita T, Fukae S, Yoshida T et al. Remitting seronegative symmetrical synovitis with pitting edema syndrome induced by pembrolizumab in patient with urothelial carcinoma. IJU Case Rep. 2022; 5: 219–222. Ngo L, Miller E, Valen P, Gertner E. Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report. Journal of Medical Case Reports. 2018; 12:48. Abdel-Wahab N, Shah M, Lopez Olivo MA, Suarez-Almazor ME. Use of Immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoinmune diseases: A systematic review. Ann Intern Med. 2018; 168: 121-130. Tison A, Quéré G, Misery L, Funck-Brentano E, Danlos FX, Routier E et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autimmune Disease: A Natiowide Multicenter Cohort Study. Arthritis Rheumatol. 2019; 71: 2100-2111. Triggianese P, Novelli L, Galdiero MR, Chimenti MS, Conigliaro P, Perricone R et al. Immune checkpoint inhibitors-induced autoimmunity: The impact of gender. Autoimmun Rev. 2020; 19(8): 102590. Suarez-Almazor ME, Pundole X, Abdel-Wahab N. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic and renal toxicities from checkpoint inhibitors. Support Care Cancer. 2020; 28 (12): 6159-6173. Nguyen T, Maria ATJ, Ladhari Ch, Palassin P, Quantin X, Lesage C et al. Rheumatic disorders associated with immune checkpoint inhibitors: What about myositis? An analysis of the WHO’s adverse drug reactions database. Ann Rheum Dis. 2020; pp.annrheumdis-2020-217018. ff10.1136/annrheumdis-2020-217018ff. ffhal-03515309f. Capelli LC, Brahmer JR, Forde PM, Le DT, Lipson EJ, Naidoo J et al. Clinical presentation of immune ckeckpoint inhibitor-inducedinflammatoryarthritis differs by immunotherapy regimen. Semin Arthrtis Rheum. 2018; 48(3): 553-7. Ghosh N, Tiongson MD, Stewart C, Chan KK, Jivanelli B, Cappelli L et al. Ckeckpoint inhibitor-Associated Arthritis: A Systemic Review of Case Reports and Case Series. J Clin Rheumatol. 2021; 1;27(8):e317-e322, Calabrese LH, Calabrese C. The immunopathogenesis of rheumatic immune adverse events from checkpoint inhibitors: prospects for targeted therapy. Curr Opin Rheumatol. 2020; 32: 175-183. Cappelli LC, Bingham CO, Forde PM, Anagnostou V, Brahmer J, Lipson EJ et al. Anti-RA33 antibodies are, present in a subset of patients with immune checkpoint inhibitor-induced inflammatory arthritis. RMD Open. 2022; 8: e002511. doi:10.1136/ rmdopen-2022-002511. Arnaud-Coffin P, Maillet D, Gan HK, You B, Dalle S, Péron J. A systematic review of adverse events in randomized trials assessing immune checkpoints inhibitors. Int J Cancer. 2019; 145 (3): 639-48. Roberts J, Smylie M, Walker J, Basappa NS, Chu Q, Kolinsky M et al. Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis. Clin Rheumatol. 2019; 38: 1513-1519. Leipe J, Christ LA, Arnoldi AP, Mille E, Berger F, Heppt M et al. Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open. 2018; 4(2): e000714. Xu J, Xiao L, Zhu J, Qin Q, Fang Y, Zhang JA. Methotrexate use reduces mortality risk in rheumatoid arthritis: A systematic review and meta-analysis of cohort studies. Semin Arthritis Rheum. 2022; 55:152031. Haanen J, Ernstoff MS, Wang Y, Menzies AM, Puzanov I, Grivas P et al. Autoimmune diseases and immune-checkpoint inhibitors for cancertherapy: review of the literature and personalized risk-based prevention strategy. Annals of Oncol. 2020; 31(6): 724-744. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5005235","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":352236680,"identity":"c53abf0b-bfcf-4d0f-85b3-5c4ab3ee8985","order_by":0,"name":"María Victoria Collado","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIie3PMWrDMBSAYYlX1MVGa0PJHRS89yJdVArZBBkNdRKBwVkKXm0o6RXcxXOMwF4COUAX+wbO5jGyoUvBUbIFoh8k0EPf8BCy2W4x0KdeICwBqq71+wlIM+FMk0fCJ8m+n2ADQX+EOuzZjfqngbAKmpqzl2kMDpul2+Ur3WjS+fk4UcRjnL17aUgW/JhXIlFY4s/97yiZhA554gzeMgVZkealkJoAjoxkrQmahe5XKb5NhMJAlCYPHrgyEJmZDLtU/S5znJQ78aNJcW4XQlVTt/7HNKaqRG2wEtuDKurOHyf/U8O9u/i/bnXNZ5vNZruTTgZeWVTzVbcwAAAAAElFTkSuQmCC","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":true,"prefix":"","firstName":"María","middleName":"Victoria","lastName":"Collado","suffix":""},{"id":352236681,"identity":"1c13d16f-06ba-4cdd-874b-0dc08127ff12","order_by":1,"name":"María Natalia Gandur","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"Natalia","lastName":"Gandur","suffix":""},{"id":352236682,"identity":"b91ed0bc-1f4c-4b77-877d-8e4a14fe2707","order_by":2,"name":"Stella Maris Ranuncolo","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Stella","middleName":"Maris","lastName":"Ranuncolo","suffix":""},{"id":352236683,"identity":"6a6d89a3-744e-43e7-a770-7aa96ad3f1b5","order_by":3,"name":"Silvana Cugliari","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Silvana","middleName":"","lastName":"Cugliari","suffix":""},{"id":352236684,"identity":"a60ba430-7f89-4819-8be5-a9583db4ee13","order_by":4,"name":"Mónica Castro","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Mónica","middleName":"","lastName":"Castro","suffix":""},{"id":352236685,"identity":"615851e9-9fd7-4cc5-b7bd-ffefdb30701f","order_by":5,"name":"Viviana Cuartero","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Viviana","middleName":"","lastName":"Cuartero","suffix":""},{"id":352236686,"identity":"70226ae2-c5c2-4558-90ce-937cc583bb03","order_by":6,"name":"Valeria Cáceres","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"","lastName":"Cáceres","suffix":""},{"id":352236687,"identity":"6668dc7a-5851-438d-9188-2ccae00502f8","order_by":7,"name":"Mercedes del Valle Serrano","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Mercedes","middleName":"del Valle","lastName":"Serrano","suffix":""},{"id":352236688,"identity":"a7bc038e-a3b4-45a7-96c4-f6f0f1fb3bef","order_by":8,"name":"Ignacio Casas Parera","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Ignacio","middleName":"Casas","lastName":"Parera","suffix":""},{"id":352236689,"identity":"c1f9348b-9938-4251-b869-1708b66391c3","order_by":9,"name":"Gabriela Cinat","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"","lastName":"Cinat","suffix":""},{"id":352236690,"identity":"b36123bd-13c0-4e36-acea-65a5ee31ea06","order_by":10,"name":"Marta Zerga","email":"","orcid":"","institution":"Instituto de Ocología \"Ángel H. Roffo\" Facultad de Medicina Universidad de Buenos Aires.","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Zerga","suffix":""}],"badges":[],"createdAt":"2024-08-30 16:47:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5005235/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5005235/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":72763312,"identity":"94fb6522-04c4-4d1f-8690-799b1f517293","added_by":"auto","created_at":"2025-01-02 00:01:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":543489,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5005235/v1/edef0973-8e0c-4bea-bb11-0d9a59119034.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Assessment of immune-related rheumatological adverse events in a monovalent oncology center in Argentina","fulltext":[{"header":"Background","content":"\u003cp\u003eImmunotherapy drugs, named as Immune Checkpoint Inhibitors (ICI), play their role by blocking checkpoint proteins from binding with their corresponding partner proteins. This prevents the initiation of the “off” signal allowing T lymphocytes to identify malignant tumor cells.\u003c/p\u003e \u003cp\u003eThese include cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Immune checkpoints play a role in maintaining tolerance to self antigens in healthy individuals, preventing excessive activation of the immune system. However, the activation of the immune system can lead to the complication of loss of tolerance and the emergence of inflammatory or de novo autoimmune manifestations, or reactivation of pre-existing autoimmune diseases, known as immune-related adverse events (IrAEs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe IrAEs can affect any organ [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Its toxicity profile may vary depending on the type of ICI (for example, it has been reported that arthralgia and arthritis are more common in patients treated with PD-1/PD-L1 inhibitors than with anti-CTLA-4) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and also whether ICIs are given as monotherapy or as a combined therapy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The IrAEs can appear while the patient is receiving the ICI treatment. They can also persist o start following their discontinuation (the latter being a common feature of the reumathologic manifestations) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Depending on the IrAE severity, patients may require the ICI treatment suspension or evenmore an immunosuppressive therapy. There are still several answered questions, among others, the immune-related rheumatologic adverse events (IrRAEs) characteristics.\u003c/p\u003e \u003cp\u003eAccording to reported data, the estimated prevalence of IrRAEs ranges from 1.5 to 22% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It is suggested that there could be an underdiagnosis of this type of adverse events, which could be partially explained due to disparities in the definition of rheumatologic symptoms or their severity between oncology and rheumatology guidelines. Additionally, it should be considered the potencial benefit of a deeper exchange between the clinical oncology and rheumatology departments.\u003c/p\u003e \u003cp\u003eTherefore, the primary objective of this study was to describe the characteristics of the IrAE with a rheumatologic nature in oncology patients undergoing ICI treatment, who were evaluated at the Rheumatology Department of the Angel H. Roffo Institute, an Argentinian monovalent oncology center. The secondary objectives were to assess the treatment and evolution of IrRAEs, as well as the continuity or discontinuation of oncologic treatment following their development. Additionally, the study aimed to describe cases where pre-existing rheumatologic diseases (PRD) were the reason for not initiating ICI treatment.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003e The investigation has been conducted according to the principles expressed in the Helsinki Declaration and after the Ethics Committee on Research Protocols approval of the Institute of Oncology Ángel H. Roffo, School of Medicine, University of Buenos Aires.\u003c/p\u003e\u003cp\u003eA descriptive and retrospective study was conducted at a monovalent Oncology hospital affiliated with the University of Buenos Aires, the Ángel H. Roffo Institute of Oncology. All patients aged \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e≥\u003c/span\u003e 18 years, undergoing treatment or planning to initiate treatment with ICI, referred to the Rheumatology Department by the corresponding treating oncologist, were included. They were recruited during the period November 2019 and July 2022. The COVID19 pandemia had a significant impact on the recruitment.\u003c/p\u003e\u003cp\u003e Patients included in the study were either initiating treatment or had received one or more doses of ICI (anti-CTLA-4: ipilimumab; anti-PD-1: nivolumab, pembrolizumab; anti-PD-L1: avelumab), either as a single drug or in combination according to oncologic indications approved by the National Administration of Drugs, Food, and Medical Technology of Argentina.\u003c/p\u003e\u003cp\u003eFor the analysis of the characteristics of IrRAEs, patients who did not initiate ICI treatment due to PRD, were excluded.\u003c/p\u003e\u003cp\u003e The total number of ICI treatments performed at the Institute during the same time period of analysis of this study, was obtained from a retrospective analysis of the Day Hospital nursing records.\u003c/p\u003e\u003cp\u003eThe request for immunological laboratory tests was individualized based on the findings of the patient's interview and clinical evaluation. The study was approved by the Ethical Comittee of the Institute of Oncology “Ángel H. Roffo”. All patients included were informed regarding the study scope and objectives. Each one of them signed the corresponding informed consent.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThis is a descriptive, retrospective, observational study. Data was stored digitally using Microsoft Office® Excel. For descriptive statistics, Microsoft® Excel was employed. Continuous variables were described using either mean and standard deviation or median and range, depending on their distribution.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom November 2019 to July 2022, 190 patients were evaluated in the Rheumatology Department, of which 42 patients (22%) met the inclusion criterias for this study: 7 were referred for evaluation before the initiation of the ICI therapy and 35 were referred for having developed rheumatologic symptoms after the initiation of the ICI treatment. During the same time frame, 159 patients underwent ICI treatment at our Institute according the retrospective analysis of the nursing records of the Day Hospital (Table 1). The median number of ICI treatments for the total treated patients was 3 (1-37).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Oncological patients evaluated by the rheumatological department.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive table of the number of ICI treatments conducted at the Angel H. Roffo Oncology Institute from November 2019 to July 2022, based on the retrospective analysis of nursing records. The table includes the number of patients evaluated by the rheumatology department and the number of patients who developed immune-mediated rheumatological adverse events.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.0759%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eType of tumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMelanoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRenal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBladder\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProstate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.72175%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH and N\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBreast\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervix\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphomas\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eColon\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOthers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.23946%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.0759%;\"\u003e\n \u003cp\u003eNumber of ICI treatments conducted at the Angel H. Roffo Oncology Institute\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.72175%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.23946%;\"\u003e\n \u003cp\u003e159\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.0759%;\"\u003e\n \u003cp\u003eNumber of patients with ICI therapy assessed in Rheumathology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.72175%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.23946%;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.0759%;\"\u003e\n \u003cp\u003eNumber of patients with IrRAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.72175%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.39629%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6.23946%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eReferences: ICI = immune checkpoint inhibitors, IrRAE = immune-related rheumatological adverse events, H and N = Head and Neck.\u003c/p\u003e\n\u003cp\u003eDescriptive table of the number of ICI treatments conducted at the Angel H. Roffo Oncology Institute from November 2019 to July 2022, based on the retrospective analysis of nursing records. The table includes the number of patients evaluated by the rheumatology department and the number of patients who developed immune-mediated rheumatological adverse events.\u003c/p\u003e\n\u003cp\u003eAmong the group of 7 patients referred for evaluation before the initiation of the ICI therapy, 3/7 were diagnosed with PRD: Systemic sclerosis, gout and polymyalgia rheumatica (PMR). Only the patient with PMR was capable of starting the ICI treatment. The other 4/7 patients, evaluated before the initiation of ICI who also started ICI treatment, were diagnosed with osteoarthritis (n=1/4) and oncologic progression (n=3/4) as the cause of rheumatologic symptoms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, out of the 159 patients who received ICI treatment at the institute, 40 were evaluated in rheumatology (25%). Of the 40 patients who received ICI treatment, 25/40 (62%) were male. The mean age was 64 years (SD \u0026plusmn; 11.54). The diagnosed cancer types were renal carcinoma (n=15/40), melanoma (n=13/40), bladder cancer (n=8/40), Hodgkin\u0026apos;s lymphoma (n=1/40), lung cancer (n=1/40), colon carcinoma (n=1/40), and cervical cancer (n=1/40). Four patients (4/40) received a combination of anti-CTLA-4 and PD-1, and 36/40 were treated with single anti-PD-1 or single anti-PD-L1. The most frequently prescribed ICIs were Pembrolizumab (n=17) and Nivolumab (n=15). Twenty-five out of 40 patients received other oncologic treatments before the initiation of ICI therapy.\u003c/p\u003e\n\u003cp\u003eThe most common rheumatologic symptom that led patients to the Rheumatology Department was arthralgia (16/40 cases).\u003c/p\u003e\n\u003cp\u003eOut of the 35/40 patients evaluated in the Rheumatology Department due to \u0026nbsp;rheumatologic symptoms following the initiation of ICI treatment, in 16/35 cases the cause of those symptoms was an IrRAE.\u003c/p\u003e\n\u003cp\u003eThe diagnosed IrRAEs were: PMR (n=4/16), ICI-associated arthralgia (n=4/16), ICI-associated inflammatory arthritis (n=2/16), the SR3PE syndrome (remitting symmetrical seronegative synovitis with pitting edema) (n=2/16), myositis (n=1/16), and 3/16 cases were patients with PRD [2/3 Ankylosing Spondylitis (AS) and 1/3 Rheumatoid Arthritis (RA)] who expirienced an exacerbation of their previous disease.\u003c/p\u003e\n\u003cp\u003eNine out of the 16 patients with IrRAEs were male. The median number of ICI treatments received until the development of IrRAEs was 6 (2-30). All the patients had negative antibodies, except for patients with PRD and other two patients. One of these patient with knee arthritis had a positive antibody anti-cyclic ctrullinated peptide (ati-CCP). He developed a complete response to a moderate dose of corticosteroid and later negativized the anti-CCP. \u0026nbsp;The other patient had arthralgia and elevated anti-nuclear antibody (ANA) with negative extractable nuclear antigens, anti-DNA, rheumatoid factor, and anti-CCP. He did not present synovitis or extra-articular manifestations and responded well to NSAID treatment. Seven of these patients had a first-degree relative with autoinmmune disease including rheumatoid arthritis (2), systemic erythematosus s\u0026iacute;ndrome (1), ankylosing spondylitis (1), type I diabetes (1), vitiligo and type I diabetes (1) and hypothyiroidism (1). The remaining 19/35 patients presented as the cause of their consultation symptoms: non-rheumatologic irRAEs (n=3/19), Osteoarthritis (OA, n=6/19), oncologic progression (n=5/19), and in 5 cases: arthralgias (n=2/19), soft tissue rheumatism (n=2/19), and low back pain (n=1/19), whose association with ICI could not be definitely determined due to the lack of \u0026nbsp; complementary studies needed for the establishment of that correlation.\u003c/p\u003e\n\u003cp\u003eThe patient diagnosed with PMR before the initiation of ICI did not experience an exacerbation of her disease during the ICI treatment.\u003c/p\u003e\n\u003cp\u003eSeven out of the 16 patients with IrRAEs, also experienced non-rheumatologic IrAE (endocrinological, dermatological and gastrointestinal (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOut of the 16 patients with IrRAEs, 11 received corticosteroids with doses of meprednisone mild \u0026lt; 7.5 mg (n=2/11), moderate 7.5-30 mg (n=5/11), and high \u0026gt; 30 mg/day (n=4/11). Five out of these patients (5/11), in addition to corticosteroids received as well conventional DMARDs: single Methotrexate or combination of Methotrexate and Hydroxicloroquine. Myositis was the most severe IrRAE. The patient required hospitalization, treatment with intravenous corticosteroids, Mycophenolate mofetil and anti-TNF (Infliximab). The patient died due to muscle weakness and respiratory failure. The other 5/16 patients only received treatment with NSAIDs. (Table 2). Therefore, out of the total patients with IrRAEs, 11/16 patients (69%) required corticosteroid treatment, of which 5/11 also required conventional DMARDs (31%). Regarding the response to this treatment: 6/11 had a complete response, two had a partial response (2/11) and 3/11 showed no response.\u003c/p\u003e\n\u003cp\u003eOf the 5 patients who received conventional DMARDs, two required permanent discontinuations of ICI treatment, while the other 3 only required temporary suspension. Out of the 5/16 patients treated only with NSAIDs, 3/5 had a complete response, and 2/5 did not respond. On the other hand, it is important to emphasize that the 3/16 patients with PRD were able to continue with ICI treatment (Table 2).\u003c/p\u003e\n\u003cp\u003eThe follow-up of patients after IrRAEs treatment showed 7/16 patients (44%) were able to continue the ICIs therapy, 3/16 (19%) had to temporaly suspend it and 6/16 (37%) permanently discontinued it (Table 2).\u003c/p\u003e\n\u003cp\u003eAmong the 4 patients with a combination of anti-CTLA-4/PD-1, 2/4 (50%) experienced IrRAE (one PMR and other grade 2 arthalgia) and 2 had more severe non rheumatologic IrAEs (grade 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn cases of rheumatologic manifestations not associated with ICI, the use of corticosteroids was not necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePatients with immune-mediated rheumatological adverse events.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003ePatient N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eOncological Diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 28px;\"\u003e\n \u003cp\u003eICI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRheumatological consultation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eImmunological laboratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eRheumatological diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eNon rheumatological IrAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eIrRAE grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eIrRAE treatment (corticosteoids maximal initial doses)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 38px;\"\u003e\n \u003cp\u003eIrRAE follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eICI Treatment decision following IrRAE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eAnti CCP- ANA- ENA- \u0026nbsp; LA- \u0026nbsp; \u0026nbsp;ACL- \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;normal C3 and C4 levels\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 20 mg/day,\u003c/p\u003e\n \u003cp\u003eMethotrexate \u0026nbsp;15 mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eTemporary suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eWeakness in the shoulder girdle and hands arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp; anti CCP- ANA- ENA- ANCA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePolymyalgia rheumatica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 40 mg/day, Methotrexate \u0026nbsp;15 mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eTemporary suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands\u003c/p\u003e\n \u003cp\u003earthralgia\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eANA 1/1280 nuclear homogeneous ENA- \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;anti dsDNA- RF- \u0026nbsp; \u0026nbsp; \u0026nbsp; anti CCP- LA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthalgias\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNSAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePermanent suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eI+N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eWeakness in both shoulder girdles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp; anti CCP- ANA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePolymyalgia Rheumatica\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eTransaminitis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 12 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eWeakness in both shoulder girdles.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp; anti CCP- ANA- ENA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePolymyalgia Rheumatica\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eVitiligo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 20 mg/day,\u003c/p\u003e\n \u003cp\u003eMethotrexate \u0026nbsp;15 mg/week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePermanent suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands\u003c/p\u003e\n \u003cp\u003earthralgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp; anti CCP-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthalgias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eParacetamol \u0026nbsp; \u0026nbsp;1 g/day,\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; NSAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eMelanoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eWeakness in both shoulder girdles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp;ANA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;Polymyalgia\u003c/p\u003e\n \u003cp\u003eRheumatica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eVitiligo\u0026nbsp;hipothyroidysm\u003c/p\u003e\n \u003cp\u003eAdrenal\u003c/p\u003e\n \u003cp\u003einsufficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 10 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eTemporary suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands edema with godet and arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp;Anti CCP- ANA- \u0026nbsp; Anti-SS-A/Ro- Anti-SS-B/La-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eSR3PE\u003c/p\u003e\n \u003cp\u003eSyndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 16 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePermanent suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eAnti CCP+ RF- \u0026nbsp; \u0026nbsp; ANA- \u0026nbsp; \u0026nbsp;Anti-SS-A/Ro- Anti-SS-B/La-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePre-existing rheumatological disease exacerbation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eDyarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMethotrexate 7,5 mg/week\u003c/p\u003e\n \u003cp\u003eHCQ 400 mg/day, \u0026nbsp; \u0026nbsp; \u0026nbsp;MPD 4 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eTemporary suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAchilles enthesitis and sacroiliitis\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHLA B27+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePre-existing rheumatological disease exacerbation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNSAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eProstate and renal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands edema with godet and arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp;Anti CCP-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;RS3PE\u003c/p\u003e\n \u003cp\u003eSyndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eTransaminitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eMPD 4 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eBladder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eKnees arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eAnti CCP+ (later \u0026ndash;) RF- ANA- ENA- normal C3 and C4 levels ANCA -\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthritis \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003ePharmacodermy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eBethametasone, later MPD 8 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePermanent suspension\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eBladder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eInflammatory low back pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHLA B27+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003ePre-existing rheumatological disease (AS) exacerbation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eHypophysitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNSAI \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eDXM 8 mg/d\u0026iacute;a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHodgkin Lymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eMuscle weakness, dysnea, hands arthralgia, chest pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eCan\u0026acute;t do it\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eMyositis, miocarditis, pneumonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003eDXM 8 mg/day MMF, Infliximab \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;5 mg/Kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eCervix\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands and knees arthalgias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp;Anti CCP- ANA- ENA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthralgias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003ePregabalin 150 mg/day NSAI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;D vitamin 100000 IU/month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eColon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 76px;\"\u003e\n \u003cp\u003eHands and knees arthalgias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRF- \u0026nbsp; \u0026nbsp; \u0026nbsp;Anti CCP-ANA- ENA-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eArthralgias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 94px;\"\u003e\n \u003cp\u003ePregabalin 75 mg/day \u0026nbsp; \u0026nbsp; \u0026nbsp; NSAI \u0026nbsp; opioid pain reliever 50 mg/day.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eContinued treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eDescription of the 16 cases of immune-related rheumatological adverse events (IrRAEs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReferences:\u003c/strong\u003e ACL= anti cardiolipin antibodies, ANA = antinuclear antibody, ANCA= antineutrophil cytoplasmic antibody, AR= rheumatoid arthritis, AS= ankylosing spondylitis, CCP= anti cyclic citullinated peptide, C3= complement factor 3, C4 = complement factor 4, CR = complete response, \u0026nbsp; anti dsDNA= double stranded DNA antibody, DXM= dexamethasone, ENA= anti-extractable nuclear antigen antibodies, HCQ= hydroxychloroquine, HLA B27 = B*27 Human Leucocyte Antigen, ICI = Immune checkpoint inhibitor, IM = intramuscular, I= Ipilimumab, \u0026nbsp;IrRAE = \u0026nbsp;immune-related rheumatological adverse event, IU = International Units, LA= lupus anticoagulant, \u0026nbsp;anti-La antibody = anti SS-B/La, MPD = meprednisone, mg = milligram, MMF= mycophenolate mofetil, N = Nivolumab, NSAI = Non-steroidal anti-inflammatories, NR = non response, PR = partial response, P= Pembrolizumab, RF= rheumatoid factor, \u0026nbsp;anti Ro antibody = anti SS-A/Ro, RS3PE= remitting seronegative symmetrical synovitis with pitting edema syndrome.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study reports the frequency and characteristics of irRAE from a monovalent oncology center in Argentina, aiming to contribute data to enhance knowledge in an area where there is a scarcity of such information.\u003c/p\u003e\n\u003cp\u003eTwenty five percent (40/159) of the total ICI treated patients in the Institute of Oncology \u0026Aacute;ngel H. Roffo were refered to the Rheumatologic Departure because of rheumatologyc symptoms development. The irRAEs were the cause of these symptoms in 40% (16/40) of the patients. When considering the total number of patients treated with ICI at our institute, it is observed that 10% (16/159) of them experienced IrRAEs, nevertheless it is not a prospective study, so not all patient were referred to the Rheumatology Department. In this regard, it might be considered that the treating oncologist requested rheumatology evaluations for cases with more severe symptoms or a history of rheumatologic disease. However, the percentage of patients referred to the Rheumatology Department is similar to that reported by Kostine et al., who prospectively studied 524 patients receiving ICI treatment, with 35 being refered to rheumatology due to IrRAEs (prevalence 6.6%) [8].\u003c/p\u003e\n\u003cp\u003eOn the other hand, in 40% (16/40) of the patients referred to the rheumatology department who received ICI treatment, IrRAEs were confirmed. This implies that oncologists also referred mild severe non-inflammatory rheumatologic manifestations or cases mimicking rheumatologic diseases that required the rheumatologist evaluation for differential diagnosis. This aligns with findings reported by Mooradian MJ et al., who assessed 29 oncology patients from a single center, where 18 presented with IrRAEs, and 11 had another cause for musculoskeletal symptoms [9]. Therefore, it would be expected that collaboration as teamwork between rheumatologists and oncologists is promoted, there will be an improvement in the IrRAEs report and the patients monitoring.\u003c/p\u003e\n\u003cp\u003eThe most frequently detected IrRAEs in this study were ICI-associated arthralgia, ICI-associated arthritis (6/16 = 37.5%) and PMR (4/16 = 25%), consistent with the literature\u003csup\u003e \u003c/sup\u003e[1, 7, 10]. However, two cases of SR3PE were also identified, which has been less frequently reported in the literature\u003csup\u003e \u003c/sup\u003e[11, 12]. And three cases of exacerbations of PRD, which in general, are excluded from clinical studies. In two of these cases, the PRD was unknown to the patient and was identified during the rheumatological evaluation before the initiation of the ICI treatment. In three patients with PRD, an exacerbation of the preexisting disease was observed; nevertheless, all of them were able to continue the ICI treatment. It has been reported that patients with PRD, when treated with ICI, are more prone to develop IrRAEs, as exemplified by the study of Abdel-Wahab et al. This work reported the evaluation of 123 patients with cancer and PRD at the start of ICI treatment. It was observed that 75% of the analyzed patients had IrRAEs (41% an exacerbation of the underlying disease, 25% de novo IrRAE, and 9% both) [13]. This suggests that it would be advisable to have a prior assessment and multidisciplinary collaboration with a rheumatologist for the detection of PRD or follow-up in case of PRD because more than half of the cases may experience an exacerbation of the PRD. Despite this, with the proper control, it does not imply a contraindication to initiate the ICI treatment [1, 13-14].\u003csup\u003e \u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe 56.25% of IrRAEs in this study occurred in men. Angelopoulou et al. evaluated 13 retrospective studies, reporting a total of 258 ICI-treated patients who developed IrRAEs, of which 154 were men (59.68%), suggesting that these manifestations appear to be more common in men than in women [1]. On the other hand, Triggianese et al. conducted a systematic review to assess the gender impact on IrRAEs by ICI and reported that Sicca/Sj\u0026ouml;gren\u0026apos;s syndrome was observed in 50% of men compared to the primary disease, which affects only 5% of men [15]. More studies are needed to determine if this could be a difference between primary rheumatologic disease and IrRAE and to what extent other factors such as tumor histology or the type of ICI prescribed influence this phenomenon.\u003c/p\u003e\n\u003cp\u003eAlthough most IrRAEs were of mild to moderate severity, in the case of a diagnosis of myositis, the patient passed away due to progression of muscular weakness and respiratory failure despite immunosuppressive treatment and discontinuation of ICI. The reported incidence of myositis is low (1-6%) [16], but it is known to involve greater severity, especially in cases of triple M syndrome: myositis, myocarditis, and myasthenia gravis. It requires aggressive immunosuppressive treatment and often needs permanent discontinuation of ICI [17]. \u003c/p\u003e\n\u003cp\u003eIf PRD is excluded, most of de novo IrRAEs (10/12) (83%) were seronegative. In accordance with this finding, it is known that antibodies are usually absent, in the de novo IrRAEs [8, 18. 19]. Angelopoulou et al. reported seropositivity in only 18.48% of the 211 patients tested in 15 evaluated retrospective studies. This seems to be another characteristic of IrRAEs compared to primary rheumatologic diseases. It could be speculated that there is a T CD8+ cell predominat activity in IrRAEs. Furthermore novel IrRAEs antibodies should be teasted beyond the ones currently available in daily practice as it being done in some studies\u003csup\u003e \u003c/sup\u003e[20, 21]. \u003c/p\u003e\n\u003cp\u003eThe combinated anti-CTLA-4 and anti-PD-1 treatment showed a higher risk of IrRAEs and greater severity of them than monovalent treatments. In the systematic review by Arnaud-Coffin P et al., which included 16,485 patients, they determined grade 3 IrRAEs in 14% of patients treated with anti-PD (L)-1, 34% in those treated with anti-CTLA-4, and 55% in those receiving combined treatment. In addition to the higher frequency, they also reported a higher grade of severity (\u0026gt; 3) of IrRAEs in patients under combined treatment\u003csup\u003e \u003c/sup\u003e[22]. \u003c/p\u003e\n\u003cp\u003eRegarding the type of treatment, distinguishing IrRAEs from rheumatologic manifestations not associated with ICI limited the use of corticosteroids to cases of IrRAEs. Treatment with conventional DMARDs for IrRAEs or PRD helped improve symptoms control and allowed the continuation of ICI treatment in the majority of cases. In this study, 69% of patients received corticosteroid treatment, and 31% additionally required treatment with DMARDs, as reported in the literature. In this regard Angekopoulou F et al. evaluated 256 patients with musculoskeletal IrRAEs, with 70.52% and 18.45% requiring the above mentioned treatments respectively\u003csup\u003e \u003c/sup\u003e[1]. In our study, the most commonly used DMARD was methotrexate, and in the case of myositis, high-dose corticosteroid treatment, immunosuppressive therapy, and a biological DMARD were prescribed based on the severity of the condition. Leipe et al. reported in their study that methotrexate is a safe and effective drug as a corticosteroid-sparing agent in the treatment of ICI-induced arthritis\u003csup\u003e \u003c/sup\u003e[23, 24]. In rheumatology, the use of lower doses of corticosteroids and the use of DMARDs allowes to minimizing long-term damage and increasing patient survival [25]. Given that the survival of cancer patients is becoming increasingly prolonged due to new therapies, the increased reporting of IrRAEs will allow us to select the best treatments for them. This consideration should not only focus on immediate outcomes but also consider the long-term consequences of such treatments. Additionally, strategies for preventing IrRAEs in the case of PRD can be planned, as described in the report by Haanen J and col\u003csup\u003e \u003c/sup\u003e[1, 26]. \u003c/p\u003e\n\u003cp\u003eThe 63% of patients were able to continue the ICI treatment, indicating that in most cases, IrRAEs could be managed. This observation is in accordance with findings reported in the literature [1, 8-9]. \u003c/p\u003e\n\u003cp\u003eWe can consider as limitations of the current study the retrospective evaluation and a potential selection bias due to the non-systematic rheumatological assessment of the oncological patients who received ICI therapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we observed that 1 in 4 patients exposed to ICI in our institute presented rheumatologic symptoms requiring referral to the rheumatology department. IrRAEs was diagnosed in 1 of 10 of these cases after rheumatologist evaluation, emphasizing the importance of multidisciplinary collaboration. While most of these IrRAEs are of mild to moderate severity, in some cases, they can be severe and even life-threatening. Combined treatment with anti-CTLA-4 and anti-PD-1 posed a higher risk of IrAEs and increased risk of more severe IrAE. Rheumatological assessment prior to ICI initiation treatment contributed to identifying previously unknown pre-existing rheumatic conditions. The combinated follow-up by rheumatologists and oncologists facilitated the treatment of exacerbations in pre-existing rheumatic conditions and de novo IrRAEs, attempting to allow concurrent ICI treatment whenever possible. Distinguishing between IrRAEs and rheumatological manifestations not associated with ICI therapy alowed to restrict the use of corticosteroids to the IrRAEs cases. The addition of conventional DMARDs to IrRAEs treatment contributed to symptoms control and to continue the ICI treatment in the majority of the cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing the IrAEs treatment guidelines is essential, however, as reported cases increase, so does knowledge about various therapeutic opportunities with concomitant oncological and rheumatological treatments.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACL= anti cardiolipin antibodies\u003c/p\u003e\n\u003cp\u003eANA = antinuclear antibody\u003c/p\u003e\n\u003cp\u003eANCA= antineutrophil cytoplasmic antibody\u003c/p\u003e\n\u003cp\u003eAR= rheumatoid arthritis\u003c/p\u003e\n\u003cp\u003eAS= ankylosing spondylitis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCCP= anti cyclic citullinated peptide\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eC3= complement factor 3\u003c/p\u003e\n\u003cp\u003eC4 = complement factor 4\u003c/p\u003e\n\u003cp\u003eCR = complete response\u003c/p\u003e\n\u003cp\u003eCTLA-4 = cytotoxic T-lymphocyte antigen 4\u003c/p\u003e\n\u003cp\u003eanti dsDNA= double stranded DNA antibody\u003c/p\u003e\n\u003cp\u003eDXM= dexamethasone\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDMARDs = Disease-Modifying Antirheumatic Drugs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eENA= anti-extractable nuclear antigen antibodies\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHCQ= hydroxychloroquine\u003c/p\u003e\n\u003cp\u003eHLA B27 = B*27 Human Leucocyte Antigen\u003c/p\u003e\n\u003cp\u003eICI = Immune checkpoint inhibitor,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIM = intramuscular,\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;I= Ipilimumab,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IrRAE = \u0026nbsp;immune-related rheumatological adverse event,\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IU = International Units,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLA= lupus anticoagulant, \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eanti-La antibody = anti SS-B/La,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMPD = meprednisone,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003emg = milligram,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMMF= mycophenolate mofetil,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eN = Nivolumab,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNSAI = Non-steroidal anti-inflammatories,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNR = non response\u003c/p\u003e\n\u003cp\u003eOA= Osteoarthritis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eP= Pembrolizumab\u003c/p\u003e\n\u003cp\u003ePR = partial response\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePRD = pre-existing rheumatologic disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD-1=programmed cell death-1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD-L1=programmed cell death ligand-1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRF= rheumatoid factor \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eanti Ro antibody = anti SS-A/Ro\u003c/p\u003e\n\u003cp\u003eRS3PE= remitting seronegative symmetrical synovitis with pitting edema syndrome\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclarationsEthics approval:\u003c/strong\u003e This research was approved by the Ethics Committee on Research Protocols of the Institute of Oncology \u0026ldquo;\u0026Aacute;ngel H. Roffo\u0026rdquo;, School of Medicine of the University of Buenos Aires.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e Each one of the patients signed the corresponding informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e data generated or analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competitive interests:\u003c/strong\u003e MVC, MNG, SMR, SC, MC, VC, VC, MS, ICP, GC and MEZ declare that they have no conflict of interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNone to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCredit authorship contribution statement:\u0026nbsp;\u003c/strong\u003eMVC performed research, analyzed data and wrote the manuscript; MNG discussed p\u0026agrave;tients\u0026acute;outcome; SMR wrote the manuscript; SC, MC, VC, VC, MS, ICP, GC, MEZ discussed patients\u0026acute;outcome.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAngelopoulou F, Bogdanos D, Dimitroulas T, Sakkas L, Daussis D. 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JAMA Oncol. 2018; 4(12):1721-1728.\u003c/li\u003e\n\u003cli\u003eBraaten TJ, Brahmer JR, Forde PM, Le D, Lipson EJ, Naidoo J et al. Immune Checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2020; 79: 332-338.\u003c/li\u003e\n\u003cli\u003eKostine M, Finckh A, Bingham CO, Visser K, Leipe J, Schulze-Koops H et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann Rheum Dis. 2021; 80:36\u0026ndash;48.\u003c/li\u003e\n\u003cli\u003eKostine M, Rouxel L, Barnetche T, Veillon R, Martin F, Dutriax C et al. Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer\u0026mdash;clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Ann Rheum Dis. 2017; 77(3):393-398.\u003c/li\u003e\n\u003cli\u003eMooradian MJ, Nasrallah M, Gainor JF, Reynolds KL, Cohen JV, Lawrence DP et al. Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience. Semin Arthritis Rheum. 2019; 48(6):1127-1132.\u003c/li\u003e\n\u003cli\u003eCapelli LC, Shah AA, Bingham 3\u003csup\u003erd\u003c/sup\u003e CO. Immune-related adverse effects of c\u0026aacute;ncer immunotherapy-implications for rheumatology. Rheum Dis Clin North Am. 2017; 43: 65-78.\u003c/li\u003e\n\u003cli\u003eYoshimura A, Yamanaka K, Tadokoro R, Wakita T, Fukae S, Yoshida T et al. Remitting seronegative symmetrical synovitis with pitting edema syndrome induced by pembrolizumab in patient with urothelial carcinoma. IJU Case Rep. 2022; 5: 219\u0026ndash;222.\u003c/li\u003e\n\u003cli\u003eNgo L, Miller E, Valen P, Gertner E. Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report. Journal of Medical Case Reports. 2018; 12:48.\u003c/li\u003e\n\u003cli\u003eAbdel-Wahab N, Shah M, Lopez Olivo MA, Suarez-Almazor ME. Use of Immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoinmune diseases: A systematic review. Ann Intern Med. 2018; 168: 121-130.\u003c/li\u003e\n\u003cli\u003eTison A, Qu\u0026eacute;r\u0026eacute; G, Misery L, Funck-Brentano E, Danlos FX, Routier E et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autimmune Disease: A Natiowide Multicenter Cohort Study. Arthritis Rheumatol. 2019; 71: 2100-2111.\u003c/li\u003e\n\u003cli\u003eTriggianese P, Novelli L, Galdiero MR, Chimenti MS, Conigliaro P, Perricone R et al. Immune checkpoint inhibitors-induced autoimmunity: The impact of gender. Autoimmun Rev. 2020; 19(8): 102590.\u003c/li\u003e\n\u003cli\u003eSuarez-Almazor ME, Pundole X, Abdel-Wahab N. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic and renal toxicities from checkpoint inhibitors. Support Care Cancer. 2020; 28 (12): 6159-6173.\u003c/li\u003e\n\u003cli\u003eNguyen T, Maria ATJ, Ladhari Ch, Palassin P, Quantin X, Lesage C et al. Rheumatic disorders associated with immune checkpoint inhibitors: What about myositis? An analysis of the WHO\u0026rsquo;s adverse drug reactions database. Ann Rheum Dis. 2020; pp.annrheumdis-2020-217018. ff10.1136/annrheumdis-2020-217018ff. ffhal-03515309f.\u003c/li\u003e\n\u003cli\u003eCapelli LC, Brahmer JR, Forde PM, Le DT, Lipson EJ, Naidoo J et al. Clinical presentation of immune ckeckpoint inhibitor-inducedinflammatoryarthritis differs by immunotherapy regimen. Semin Arthrtis Rheum. 2018; 48(3): 553-7.\u003c/li\u003e\n\u003cli\u003eGhosh N, Tiongson MD, Stewart C, Chan KK, Jivanelli B, Cappelli L et al. Ckeckpoint inhibitor-Associated Arthritis: A Systemic Review of Case Reports and Case Series. J Clin Rheumatol. 2021; 1;27(8):e317-e322,\u003c/li\u003e\n\u003cli\u003eCalabrese LH, Calabrese C. The immunopathogenesis of rheumatic immune adverse events from checkpoint inhibitors: prospects for targeted therapy. Curr Opin Rheumatol. 2020; 32: 175-183.\u003c/li\u003e\n\u003cli\u003eCappelli LC, Bingham CO, Forde PM, Anagnostou V, Brahmer J, Lipson EJ et al. Anti-RA33 antibodies are, present in a subset of patients with immune checkpoint inhibitor-induced inflammatory arthritis. RMD Open. 2022; 8: e002511. doi:10.1136/ rmdopen-2022-002511.\u003c/li\u003e\n\u003cli\u003eArnaud-Coffin P, Maillet D, Gan HK, You B, Dalle S, P\u0026eacute;ron J. A systematic review of adverse events in randomized trials assessing immune checkpoints inhibitors. Int J Cancer. 2019; 145 (3): 639-48.\u003c/li\u003e\n\u003cli\u003eRoberts J, Smylie M, Walker J, Basappa NS, Chu Q, Kolinsky M et al. Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis. Clin Rheumatol. 2019; 38: 1513-1519.\u003c/li\u003e\n\u003cli\u003eLeipe J, Christ LA, Arnoldi AP, Mille E, Berger F, Heppt M et al. Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open. 2018; 4(2): e000714.\u003c/li\u003e\n\u003cli\u003eXu J, Xiao L, Zhu J, Qin Q, Fang Y, Zhang JA. Methotrexate use reduces mortality risk in rheumatoid arthritis: A systematic review and meta-analysis of cohort studies. Semin Arthritis Rheum. 2022; 55:152031.\u003c/li\u003e\n\u003cli\u003eHaanen J, Ernstoff MS, Wang Y, Menzies AM, Puzanov I, Grivas P et al. Autoimmune diseases and immune-checkpoint inhibitors for cancertherapy: review of the literature and personalized risk-based prevention strategy. Annals of Oncol. 2020; 31(6): 724-744.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune checkpoint inhibitors, immune-mediated rheumatologic adverse events, pre-existing rheumatologic disease, oncological patients","lastPublishedDoi":"10.21203/rs.3.rs-5005235/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5005235/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitors (ICIs) has changed the outcome of oncology patients. They are being used in an increasingly number of different cancer types. As a consequence, there is an enhance report of toxicity ICIs associated, named immune related adverse events. Herein we focused on the description of the Immune related Rheumatologic Adverse Events (IrRAEs) in oncological patients treated with ICIs, determining the continuity of the oncological treatment following their development, and investigating whether pre-existing rheumatologic disease (PRD) was the reason for not initiating the ICI treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eit is a descriptive and retrospective study. Included 42 oncology patients, initiating or already undergoing an ICI treatment, who were referred to the Rheumatology Department during 2019\u0026ndash;2022.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e40/159 (25%) patients that received ICI treatment at the Institute of Oncology \u0026ldquo;\u0026Aacute;ngel H. Roffo\u0026rdquo;, were evaluated by the Rheumatology Department. 16/40 experienced IrRAEs. Treatment of IrRAEs: 5/16 received non-steroidal anti-infammatory drugs, 11/16 corticosteroids (5/11 required additionally Disease-Modifying Antirheumatic Drugs (DMARDs). The IrRAEs treatment outcome was complete response (9/16), partial response (2/16) and no response (5/16). As a consequence 7/16 patients (44%) were able to continue the ICI therapy, 3/16 (19%) experienced a temporary suspension and 6/16 (37%) a permanent discontinuation. Two patients did not iniciate ICIs due to PRD.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003e25% of the total ICI treated patients developed rheumatologyc symptoms. The IrRAEs were the cause of them in 16/40 patients. Therefore 10% (16/159) of the total ICI treated patients developed IrRAEs. Most of the IrRAEs observed were mild to moderate. Only one patient, who suffered myositis, experienced a severe life-threatening IrRAE. The patients\u0026acute; evaluation at the time they started the ICI therapy allowed the diagnosis of PRD and to monitore exacerbations. More than half of the patients who developed IrRAEs were capable to continue their ICI treatment.\u003c/p\u003e","manuscriptTitle":"Assessment of immune-related rheumatological adverse events in a monovalent oncology center in Argentina","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-04 13:01:53","doi":"10.21203/rs.3.rs-5005235/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6eb1a265-8f19-4181-a6d5-b25d5b608a73","owner":[],"postedDate":"October 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-01T23:53:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-04 13:01:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5005235","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5005235","identity":"rs-5005235","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}