SERIO is a registry for adverse events of immunotherapies (immune-related adverse events, irAE).
In particular, we aim to collect cases of rare, complex and therapy-refractory adverse events as well as adverse events in special patient groups (i.e. patients with autoimmune diseases or patients with a solid organ transplant). Immunotherapies include checkpoint-inhibitors, cellular therapies, e.g. CAR T cells, and bispecific antibodies.
Our goal is to improve side effect management, gain insights into the pathogenesis of irAE, and be able to make predictions about irAE.
Who we are
SERIO is based at the Department of Dermatooncology at the University Hospital of Munich (LMU). The SERIO online register is operated in cooperation with the Paul Ehrlich Institute. Over the past 13 years, we have collected more than 1832 cases of rare, complex or very severe side effects from 27 centres in 6 countries. We cooperate with side effect specialists from all over the world.
SERIO was first initiated in 2011 by dermatooncologists from the University Hospital of Erlangen. The first documented case of SERIO dates back to 2009. A close collaboration with endocrinologists, cardiologists and gastroenterologists soon developed, which led to the initiation of our interdisciplinary Tox Board. Our cooperation with the Working Group Dermatooncolgy (ADO) includes the implementation of joint projects and the exchange of experiences.
SERIO aims to help physicians manage side effects and gain better knowledge of side effects induced by immunotherapy.
What we do
- Collect and analyze cases of rare, complex, severe and therapy-refractory adverse reactions induced by immunotherapy
- Provide physicians with recommendations for the management of irAE
- Conduct research and assist others conducting research related to irAE
1533 - irAEs 73 - centers 17 - tumor types
Case of the Month
60-year-old male patient with Nivolumab-induced polyarthritis and suspected necrotizing fasciitis
Metastatic cutaneous melanoma, stage IV, M1d (AJCC 2017), BRAF V660K/V600R/V600M mutated; metastases in the brain, right parotid, lymph nodes and soft tissue
ECOG 0
2006 Resection and lymph node resection
05/2019 Right parotid metastasis (right neck dissection)
07/2019-07/2020 Pembrolizumab adjuvant
08/2021 Recurrence (lymph node and soft tissue metastases)
08/2021-11/2021 Ipilimumab/nivolumab
11/2021-03/2022 Nivolumab, discontinuation due to recurrence (soft tissue metastasis)
05/2022-08/2023 Dabrafenib/trametinib
02/2023-08/2023 Stable disease
08/2023 Brain metastasis right temporal
09/2023-10/2023 Two cycles dacarbazine (DTIC)
10/2023 Reinduction of immunotherapy with ipilimumab/nivolumab as well as stereotactic irradiation of single cerebral metastases
12/2023 Diarrhea (approx. 10 stools/day), ICI-induced, improvement after a short prednisolone course with 1 mg/kg body weight
01/2024-04/2024 Nivolumab 240mg every 2 weeks
05/2024 Double dose of nivolumab (480mg every 4 weeks)
Approximately 1.5 weeks after receiving the double dose of nivolumab, the patient developed intermittent large joint pain (shoulders, knees, hips) and severe swelling and overheating of the right knee joint and the adjacent dorsal lower leg. Low dose cortisone (20 mg prednisolone/day) only led to a temporary, slight improvement in symptoms. He was admitted to a regional hospital. CT showed multiple air pockets on the medial head of the gastrocnemius muscle and several knee punctures excluded infectious cause. Due to the detected intraarticular air, severe pain in the right calf, swelling and overheating of the area around the right knee and reduced general condition, necrotizing fasciitis was suspected, so soft tissue surgery was performed on the right lower leg. The surgeons found an old hematoma, secretion, glassy disintegration of the m. sartorius, m. soleus and the m. gastrocnemius fascia, and an initial muscular disintegration of the medial m. gastrocnemius head. Histologically, there was no evidence of malignancy and there was no proof of streptococcus pyogenes or other bacteria. After the surgery, the patient was monitored in the intensive care unit and received clindamycin and piperacillin/tazobactam i.v. because the inflammatory parameters were elevated.
After discharge the patient presented to our oncology outpatient clinic in a wheel chair with severe pain of the knee joints, weakness and pain in the muscles, especially the shoulders and the right calf. Joints were swollen with minimal effusions. Upon induction of prednisolone (1mg/kg body weight) the pain stopped within one day and the patient could get up from the wheel chair again. The initial radiological findings were re-evaluated and synovitis was diagnosed, without evidence of necrotizing fasciitis. The effusion in the knee showed 6,200 leukocytes/µl and an aviscous consistency, without crystals or bacteria. In summary, the patient suffered from myositis and polyarthritis induced by the checkpoint inhibitor therapy and subsequently an iatrogenic infection in the area of the arthroscopic joint puncture. Prednisolone/d was tapered and methotrexate 15mg/week s.c. initiated. If this therapy does not significantly improve symptoms or the glucocorticoids cannot be tapered off, therapy with tocilizumb will be considered.
Since the patient is still suffering from the adverse event at the time of reporting and currently receives prednisolone in combination with methotrexate, the immune checkpoint inhibitor therapy is currently paused. Depending on the clinical findings, however, reinduction will be discussed later due to the advanced tumor state of the melanoma.
Rheumatic and musculoskeletal immune related adverse events (irAEs) are observed in about 10% of patients receiving immune checkpoint inhibitors (ICIs) [1]. Musculoskeletal irAEs show a large clinical spectrum [2], are often steroid-refractory [3] and frequently persist after cessation of ICI therapy [4]. Myositis is important to monitor since it can occur concomitantly with cardiomyositis[2].
In case of steroid-refractory rheumatic irAE several conventional synthetic disease-modifying antirheumatic drugs (csDMARD) have been used and so far, no specific drug has proven superiority. Methotrexate was the most frequently drug prescribed, followed by hydroxychloroquine then sulfasalazine, either as monotherapy or in combination [1]. No safety issues were described regarding long-term use of methotrexate associated with ICI in a few patients, with a median follow-up of over 1 year [5]. However, it takes around 4-8 weeks for the full effect to occur, so patients often have to continue taking a steroid in a tapering dosage during this period [1].
In severe rheumatic and systemic irAE or with insufficient response to csDMARD, biological disease-modifying antirheumatic drugs (bDMARD) may be considered, with TNF or IL-6 inhibitors being the preferred options for inflammatory arthritis[6]. However, prolonged use of TNF inhibitors can induce widespread, significant immunosuppression, which can negatively impact the antitumor efficacy of ICI therapy [7]. The anti-interleukin (IL)-6 receptor antibody, tocilizumab, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. It is reported to drastically improve symptoms for patients with severe ICI-induced polyarthritis [7].
The decision to reinduce the ICI-therapy should be based on the severity of musculoskeletal irAE, the extent of required immunosuppressive regimen and response of the irAE, the tumor dynamics, as well as therapy alternatives[1]. A pre-existing autoimmune rheumatic and/or systemic disease should not preclude the use of cancer immunotherapy. Baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, below 10 mg prednisone per day) [1].
This patient was thought to have a severe infection leading to necrotizing fasciitis, whereas his muskuloskeletal irAE quickly improved upon initiation of corticosteroids. Great care is needed before initiating immunosuppression in suspected infection. Thus, clarifying the genesis between an infectious and an autoimmune cause of the symptoms during ICI therapy is essential.
1. Kostine, M., 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(1): p. 36-48.
2. Moreira, A., et al., Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer, 2019. 106: p. 12-23.
3. Tomsitz, D., et al., Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Cancers (Basel), 2023. 15(9).
4. Schulz, T.U., et al., Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life. Eur J Cancer, 2022. 176: p. 88-99.
5. Leipe, J., et al., Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy. RMD Open, 2018. 4(2): p. e000714.
6. Grumme, L. and H. Schulze-Koops, [Rheumatological side effects of checkpoint inhibitors and their treatment]. Z Rheumatol, 2023. 82(3): p. 187-194.
7. Kim, S.T., et al., Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. Ann Rheum Dis, 2017. 76(12): p. 2061-2064.