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      Musculoskeletal and Rheumatic Diseases Induced by Immune Checkpoint Inhibitors: A Review of the Literature

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          Abstract

          Background:

          Immune checkpoint inhibitors are a new promising class of antitumor drugs that have been associated with a number of immune-related Adverse Events (AEs), including musculoskeletal and rheumatic disease.

          Methods:

          We searched Medline reviewing reports of musculoskeletal and rheumatic AEs induced by immune checkpoint inhibitors.

          Results:

          Several musculoskeletal and rheumatic AEs associated with immune checkpoint inhibitors treatment are reported in the literature. In particular, arthralgia and myalgia were the most common reported AEs, whereas the prevalence of arthritis, myositis and vasculitis is less characterized and mainly reported in case series and case reports. Other occasionally described AEs are sicca syndrome, polymyalgia rheumatica, systemic lupus erythematosus and sarcoidosis.

          Conclusion:

          Newly induced musculoskeletal and rheumatic diseases are a frequent adverse event associated with immune checkpoint inhibitors treatment

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          Most cited references55

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          Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature

          Background Immune checkpoint inhibitors (ICI) are improving prognosis in advanced stage cancers, but also lead to immune-related adverse events (IRAE). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAE have not been well characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAE to better understand prevalence and clinical characteristics. Methods Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence and treatment data were extracted and summarized. Results 1725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in pre-existing autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged from 1–43%, and myalgia was reported in 2–20%. Arthritis was reported in 5/33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with pre-existing autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. Conclusions Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs like inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with pre-existing autoimmune disease.
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            Cytokine release syndrome after radiation therapy: case report and review of the literature

            Background Cytokine release syndrome (CRS) has been reported after immunologic manipulations, most often through therapeutic monoclonal antibodies. To our knowledge, CRS after radiation therapy (RT) for cancer has not been reported before. The development of unusual clinical signs and symptoms after RT led us to investigate the possibility of CRS after RT and review the medical literature on this topic. Case presentation A 65 year-old man with untreated chronic lymphocytic leukemia and recurrent, metastatic Merkel cell carcinoma undergoing anti-programmed death 1 (PD1) immunotherapy was referred for palliative RT to sites of progressing metastases. Within hours of each weekly dose of RT, he experienced fever, tachycardia, hypotension, rash, dyspnea, and rigors. Based on clinical suspicion for CRS, blood cytokine measurements were performed 1 h after the second and third dose of RT and demonstrated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels approximately ten-fold higher than normal. These were near normal immediately prior to the third dose of RT, and resolved to normal levels 3 weeks after RT. He experienced rapid regression of irradiated tumors, with development of new sites of metastases soon thereafter. A literature review revealed no clinical cases of CRS after RT for cancer. Conclusions RT during anti-PD1 immunotherapy in a patient with underlying immune dysfunction appeared to be the putative mediator of an immune process which yielded significant increases in pro-inflammatory cytokines, and produced the clinical symptoms meeting the definition of grade 3 CRS. This case demonstrates the capability of RT to elicit immune-related adverse events.
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              Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab.

              Ipilimumab is a promising novel immunotherapy agent and is associated with a variety of immune-related adverse events (irAE). The purpose of this study was to investigate the manifestations of irAEs on body imaging in patients with advanced melanoma treated with ipilimumab. One-hundred forty-seven patients with advanced melanoma (59 women, 88 men; median age, 64.5 years) treated with ipilimumab were studied. All patients had the baseline and at least one follow-up chest/abdomen/pelvis CT or PET/CT during therapy, which were reviewed by a consensus of two radiologists blinded to the clinical data. Findings indicative of individual types of irAEs were assessed, including thyroiditis, sarcoid-like lymphadenopathy, pneumonitis, hepatitis, pancreatitis, and colitis. Among the 147 patients, 46 (31%) had radiologically identified irAEs. The time interval from the initiation of therapy to the development of irAEs was less than 3 months in 76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics did not differ between patients with and without irAEs (P > 0.18). Among the individual types of irAEs, colitis was most common (n = 28; 19%), followed by sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up scans, with a median time of 2.3 months after the detection of irAE. In conclusion, irAEs were noted on body imaging in 31% of patients with melanoma treated with ipilimumab. Colitis was the most common, followed by sarcoid-like lymphadenopathy and pneumonitis. The results call for an increased awareness of irAEs, given the expanding role of cancer immunotherapy.
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                Author and article information

                Journal
                Curr Drug Saf
                Curr Drug Saf
                CDS
                Current Drug Safety
                Bentham Science Publishers
                1574-8863
                2212-3911
                November 2018
                November 2018
                : 13
                : 3
                : 150-164
                Affiliations
                [1]Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona, , Italy
                Author notes
                [* ]Address correspondence to this author at the Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy; Tel: 00390715964200; Fax: 00390715964225; E-mail: m.luchetti@ 123456staff.univpm.it
                Article
                CDS-13-150
                10.2174/1574886313666180508122332
                6198478
                29745339
                5b463a6a-1457-4e77-a651-9d99824622c0
                © 2018 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 02 March 2018
                : 24 April 2018
                : 01 May 2018
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                immune checkpoint inhibitors,anti-pd1,anti-ctla4,nivolumab,pembrolizumab,ipilimumab,rheumatic diseases,musculoskeletal diseases

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