Noha Abdel-Wahab, MD, PhD; Mohsin Shah, MD; Maria A. Lopez-Olivo, MD, PhD; Maria E. Suarez-Almazor, MD, PhD
Note: Dr. Suarez-Almazor had full access to all of the data in the study and takes responsibility for the integrity and accuracy of the data analysis.
Acknowledgment: The authors thank Gregory F. Pratt from the Research Medical Library at The University of Texas MD Anderson Cancer Center for assisting with data acquisition.
Grant Support: Dr. Suarez-Almazor had a K24 career award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases while the study was conducted (grant AR053593).
Disclosures: Dr. Lopez-Olivo reports an Investigator Award from the Rheumatology Research Foundation outside the submitted work. Dr. Suarez-Almazor reports consultant fees from Bristol-Myers Squibb outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2073.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See . Statistical code: Not applicable. Data set: See the tables in and the .
Requests for Single Reprints: Maria E. Suarez-Almazor, MD, PhD, Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, Unit 1465, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; e-mail, email@example.com.
Current Author Addresses: Dr. Abdel-Wahab: Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, Unit 1465, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, and Department of Rheumatology and Rehabilitation, Assiut University Hospitals, Assiut Faculty of Medicine, Egypt.
Drs. Shah, Lopez-Olivo, and Suarez-Almazor: Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, Unit 1465, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
Author Contributions: Conception and design: N. Abdel-Wahab, M.E. Suarez-Almazor.
Analysis and interpretation of the data: N. Abdel-Wahab, M. Shah, M.E. Suarez-Almazor.
Drafting of the article: N. Abdel-Wahab, M. Shah, M.E. Suarez-Almazor.
Critical revision of the article for important intellectual content: N. Abdel-Wahab, M. Shah, M.A. Lopez-Olivo, M.E. Suarez-Almazor.
Final approval of the article: N. Abdel-Wahab, M. Shah, M.A. Lopez-Olivo, M.E. Suarez-Almazor.
Statistical expertise: N. Abdel-Wahab, M. Shah.
Obtaining of funding: M.E. Suarez-Almazor.
Administrative, technical, or logistic support: M.E. Suarez-Almazor.
Collection and assembly of data: N. Abdel-Wahab, M. Shah, M.A. Lopez-Olivo.
Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with frequent immune-related adverse events (irAEs) and is often not recommended for patients with concomitant autoimmune disease.
To summarize the evidence on adverse events associated with CPIs in patients with cancer and preexisting autoimmune disease.
MEDLINE, EMBASE, Web of Science, PubMed ePubs, and the Cochrane Central Register of Controlled Trials through September 2017 with no language restrictions.
Original case reports, case series, and observational studies describing patients with cancer and autoimmune disease who were receiving CPIs.
2 reviewers independently extracted data and assessed the quality of reporting.
123 patients in 49 publications were identified; 92 (75%) had exacerbation of preexisting autoimmune disease, irAEs, or both. No differences in adverse events were observed in patients with active versus inactive disease. Patients receiving immunosuppressive therapy at initiation of CPI therapy seemed to have fewer adverse events than those not receiving treatment. Most flares and irAEs were managed with corticosteroids; 16% required other immunosuppressive therapies. Adverse events improved in more than half of patients without discontinuation of CPI therapy. Three patients died of adverse events.
The quality and quantity of data were limited. Case reports typically describe unique manifestations and are not generalizable to the population at large. Because there were no prospective observational studies, incidence could not be determined.
Flares and irAEs in patients with autoimmune disease who are receiving CPIs can often be managed without discontinuing therapy, although some events may be severe and fatal. Prospective longitudinal studies are needed to establish incidence of adverse events and evaluate risk–benefit ratios and patient preferences in this population.
National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Evidence search and selection.
Table 1. Patient Demographic and Baseline Characteristics
Table 2. CPI-Related Adverse Events Reported in the Literature in Patients With Cancer and Preexisting Autoimmune Disease
Table 3. CPI-Related Adverse Events Reported in the Literature According to the Disease Activity of the Preexisting Autoimmune Disease and the CPI Therapy Used
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Yasuo Oshima MD PhD FACP, Noboru Hagino MD FACR, Masumi Hara MD PhD, Takashi Ohfuji MD
ACP Japan Chapter
February 5, 2018
Conflict of Interest:
Dr Oshima reports personal fees from Novartis Pharma K.K. and Sanofi K.K., outside the submitted work. Others contributors report no conflicts.
Parenoplastic syndrome or idiopathic autoimmune disease ?
To the editor
Symptoms or diseases clinically mimicking idiopathic autoimmune diseases called paraneoplastic syndrome are thought to be mediated by soluble factors or are a consequence of humoral or cellular immune mechanisms directed against tumour cells. Authors have reported flare of underlying autoimmune diseases as irAEs. We wonder if the reported the irAEs or flare of underlying autoimmune diseases were aligned with progression of malignant tumor or on the contrary destruction of malignant tumor cells. It would be grateful if authors could share the information.
Noha Abdel-Wahab, Mohsin Shah, Maria A. Lopez-Olivo, Maria E. Suarez-Almazor
Assiut University Hospitals, University of Texas MD Anderson Cancer Center
April 4, 2018
Thank you for your comments. Since this is a systematic review of reported cases in the literature, we are limited by the quality of information available in the original reports. Insufficient reporting of certain data was acknowledged. As such, information on the extent of tumor mass at the time of adverse events was not reported. Nevertheless, we have included only reports describing patients with an established diagnosis of autoimmune disease before initiation of checkpoint inhibitors (CPI) for concomitant cancer. We based our determination on the authors’ report, and most of these autoimmune diseases, such as psoriasis, autoimmune thyroid diseases, ulcerative colitis, Crohn disease, and multiple sclerosis, to name a few, are not generally considered paraneoplastic syndromes.(1, 2) In addition, we excluded all reports describing patients who developed any autoimmune manifestations at or after initiation of CPI if they did not have preexisting clinical symptoms and had never been diagnosed with autoimmune disease before treatment initiation. The point raised by Oshima and colleagues is intriguing. It is conceivable that larger tumor mass could produce more soluble antigens eliciting immune responses that cross react with peripheral normal tissues, and contributing to increased frequency and severity of adverse events. In the 61 patients we reported with autoimmune disease flare, flares were not aligned with tumor progression. In fact, 57% of those patients (n=30 out of 53) had no evidence of active autoimmune disease with ongoing disease symptoms at initiation of CPI for their progressive cancer. Upon CPI initiation, the underlying autoimmune disease flared after a median of 5.1 weeks. Disease flares were also associated with de novo immune related adverse events (irAEs) including hypophysitis, colitis, pneumonitis, among others in 18% (n=11 out of 61) suggesting an aberrant autoimmune activation. Complete remission of all symptoms with corticosteroids and other immunosuppressive therapies was reported in 92% (n=46 out of 50), with permanent discontinuation of CPI primarily because of irAEs in 22% (n=11 out of 51). In the 35 patients who completed their CPI treatment course, tumor ultimately progressed in 43% (n=9 out of 21). Because of the small numbers reported it is difficult to establish a relationship between toxicity and tumor progression. However, it has been suggested that the occurrence of irAEs in patients receiving CPI might be associated with better tumoral responses, as a result of enhanced upregulation of the immune system.(3)Noha Abdel-Wahab*†, MD, PhDMohsin Shah*, MDMaria A. Lopez-Olivo*, MD, PhDMaria E. Suarez-Almazor*, MD, PhD *Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; †Rheumatology and Rehabilitation Department, Assiut University Hospitals, Faculty of Medicine, Assiut, Egypt. References:1. Fam AG. Paraneoplastic rheumatic syndromes. Bailliere's best practice & research Clinical rheumatology. 2000;14(3):515-33.2. Manger B, Schett G. Paraneoplastic syndromes in rheumatology. Nature reviews Rheumatology. 2014;10(11):662-70.3. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol. 2017;35(7):785-92.
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 Autoimmune Disease: A Systematic Review. Ann Intern Med. ;168:121–130. doi: 10.7326/M17-2073
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Published: Ann Intern Med. 2018;168(2):121-130.
Published at www.annals.org on 2 January 2018
Hematology/Oncology, Hospital Medicine.
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