Background: Reports of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICPi) have recently attracted new attention to the complex interrelations of malignancies and rheumatic and musculoskeletal diseases (RMDs). Since those two entities represent two sides of a dysregulated immune response, further research on rheumatic irAEs and mechanisms underlying the better tumor response rates in irAE-affected patients may contribute to a better understanding of the different pathophysiology characterizing tumor and rheumatic disease.
Objectives: Given the heterogeneity of the patient population with rheumatic irAEs, a registry-based study has been conducted to provide first evidence regarding characteristics of rheumatic irAEs and further insights into the optimal diagnostic and therapeutic management of rheumatic irAEs.
Methods: The TRheuMa registry is a long-term, open-end observational study of a patient cohort suffering from rheumatic symptoms as a result of ICPi or other cancer therapies. The TRheuMa registry is one of the three subregistries of the MalheuR project, a registry-based study initiated in July 2018 at the at the university hospital Heidelberg to explore interrelations of malignancies and RMDs.
Results: Over 18 months, 52 of 63 patients in the TRheuMa registry were recruited with a rheumatic irAE under ICPi treatment (pembrolizumab n=21, nivolumab n=28, ipilimumab n=11, durvalumab n=1, atezolizumab n=2, avelumab n=1, history of >1 ICPi n=11). Of the 52 patients, 22 (42.3%) had non-small cell lung cancer and 23 (44.2%) had a melanoma. Eight (15.3%) patients experienced a flare of a preexisting RMD under ICPi treatment. The remaining 44 patients with de novo irAEs were characterized by rheumatoid arthritis-like (20.5%) or polymyalgia rheumatica-like (18.1%) and psoriatic or other spondyloarthritis-like phenotypes (50.0%). However, laboratory findings differed from classical RMDs with elevated CRP-levels in 73.1% particularly in psoriatic arthritis-like, but not necessarily in polymyalgia rheumatica-like irAEs. On the contrary, autoantibody positivity was very rare. The majority of patients (78.8%) showed signs of inflammation upon ultrasound examination.
Based on the severity of signs and symptoms as well as treatment response, we developed a therapeutic algorithm for rheumatic irAEs: non-steroidal anti-inflammatory drugs and/or low dosed glucocorticoids (≤10mg prednisone equivalent) as first treatment step were sufficient for 75% patients, whereas 17.3% required higher dosed glucocorticoids and 11.5% patients required further treatment with a cs- or bDMARD. In two cases ICPi-treatment was discontinued on patients’ request due to the pain and functional impairment caused by the rheumatic irAE, although a satisfactory symptom control was reached in the further course.
Complete remission of cancer was observed in 43.5% of melanoma patients, 66.7% experienced additional severe irAEs in other organ systems.
Conclusion: Overall, data from the TRheuMa-registry show that rheumatic irAEs mostly resemble classical RMDs, however show distinct characteristics. Our diagnostic and therapeutic management of rheumatic irAEs demonstrated efficacy in the majority of patients. These findings contribute to the further understanding of rheumatic irAEs and malignancies. Future research agenda includes a correlation of irAE severity with tumor response.
Disclosure of Interests: Karolina Benesova Grant/research support from: Study grants for SCREENED study by Abbvie, Novartis and Rheumaliga Baden-Württemberg, Consultant of: One-time participation in Novartis advisory board., Leonore Diekmann: None declared, Hanns-Martin Lorenz Grant/research support from: Consultancy and/or speaker fees and/or travel reimbursements: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly. Scientific support and/or educational seminars and/or clinical studies: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm, Thermo Fisher., Consultant of: see above, Karin Jordan Consultant of: Consultancy and/or speaker fees: MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Tesaro, Kreussler, Voluntis, Pfizer, Pomme-med., Jan Leipe Grant/research support from: Consultancy and speaker fees: Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB. Scientific support: Novartis, Pfizer., Consultant of: Consultancy and speaker fees: Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB. Scientific support: Novartis, Pfizer., Speakers bureau: Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB
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