First-line therapy for advanced non-small-cell lung cancer that lacks targetable mutations is platinum-based chemotherapy. Notably, immunotherapies have raised hope for a successful control of metastatic lung adenocarcinoma. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has resulted in remarkably longer survival and fewer adverse events. Pembrolizumab could relieve immunosuppression mediated by PD-1 pathway, and enhance its ability to kill tumor cells by activating T cell function [3,4,5]. However, the activated T cells will attack normal tissue, and produce crossed immune reaction which induces autoimmune inflammation. It produces irAEs similar to autoimmune diseases [6]. Although rheumatic irAE is not a common irAE, it has been paid more and more attention with the increase of immunotherapy in clinical use in recent years. For example, a large tertiary cancer center in Israel found that 14 (3.5%) of 400 patients had rheumatic irAE [7]. The incidence of rheumatic irAE is related to several factors, such as the type and dose of ICI, the combination of ICI used. Compared with patients treated with PD-1/PD-L1 inhibitors, patients treated with CTLA-4 inhibitors are more likely to have irAE [8]. In patients with pre-existing rheumatologic conditions, incluing Behcet’s syndrome, There is a risk of flare with combination ipilimumab and anti-PD1. Close monitoring is essential [9]. A study conducted by Cardona AF et al. showed that Oral ulcers which were insensitive to steroid treatment associated with immune checkpoint inhibitors might be related to both Behçet’s disease and graft versus host disease physiopathologically [10]. The use of anti PD-1 drugs will alter the immune system and cause cross-reaction with several antigens presenting in oral epithelium. It is reported that the changes of oral mucosa related to anti-PD-1 drugs are about 1% for Nivolumab and 2% for Pembrolizumab, beyond that no serious event was observed [11]. The incidence of grade 1 and grade 2 mucositis with Nivolumab and Pembrolizumab ranges from 1 to 2%. Oral mucositis caused by PD-1 seemed to be more common than CTLA-4 inhibitors, which are rare in immunotherapy in general [12].
A retrospective study showed that 42.5% of patients with grade 2 or above IrAEs who had been treated with ICIs had recurrence of the original irAEs again [13]. The first case of Behcet’s like syndrome following pembrolizumab treatment was reported that an elderly male with facial metastatic melanoma received 24 months on pembrolizumab therapy. Then he developed Behcet’s like syndrome with corneal ulcers, oral and genital ulcers.His symptoms improved after treatment with prednisone and colchicine [14]. This case we shared may be the second case of Behcet’s like syndrome associated with irAE of pembrolizumab treatment. And it is the first time to report the Behcet’s-like syndrome with oral ulcer, genital uler, phlebitis, and vision loss after pembrolimab treatment in China.
There is a certain correlation between Behcet’s syndrome and myelodysplastic-syndromes(MDS). Some patients with MDS may experience Behcet’s syndrome. It is more common with intestinal involvement and often accompanied by fever, especially with trisomy 8. However, the reason for the association between them is not clear, whether it is the autoimmune background causing MDS, or Behcet’s syndrome is the paraneoplastic state of MDS [15].
Behcet’s syndrome is an autoimmune disease based on vasculitis with diverse clinical manifestations. Due to the lack of specific experimental indicators so far, Behcet’s syndrome is easily misdiagnosed or undiagnosed. The main manifestations of Behcet’s syndrome are recurrent oral ulcer (at least three times in one year), genital ulcer, eye damage, skin damage. Besides, Behcet’s syndrome can also attack the gastrointestinal tract, heart, and peripheral blood vessels [16], its onset age was mostly 20–40 years old. The exact pathogenesis of Behcet’s Disease (BD) is still unclear with certain genetic susceptibility. Research shows that infection factors may play a role in triggering and/or continuing BD. The production or increased reactivity of pro-inflammatory components of innate immune response (TLR, neutrophils, NK cells) to these triggers may be a key step in the pathogenesis of BD. Inflammation has been comfirmed to cause a typical Behcet’s manifestations, including orogenic ulcer, uveitis, and skin damage [17]. The International Criteria for BD (ICBD) in 2014 (Table 1) is used to establish classification criteria of BD. It shows a total score of 4 points or more can be diagnosed as Behcet’s disease [18].The symptoms of this case are very similar to Behcet’s disease, but it is not enough to diagnose Behcet’s disease at present.It requires further observation and follow-up. Glucocorticoids are given to suppress immunity, reduce inflammation and relieve symptoms.
Approximately 10% of cancer patients receiving ICIs treatment present rheumatic and musculoskeletal irAEs [19]. According to the type and severity of adverse reactions in rheumatism, different treatment methods are adopted and different doses of corticosteroids are used. For moderate or severe cases, it is recommended to stop ICI treatment and refer to a rheumatologist. High-dose corticosteroids, intravenous immunoglobulin, human interleukin 6 receptor inhibitor, tumor necrosis factor-α inhibitor and/or plasma exchange may be considered if necessary [20].
At present, although exponentially increasing ICIs are used in malignant melanoma, lymphoma, renal cancer, lung cancer and other cancers, irAEs can not be ignored, especially the rare rheumatic manifestations. We should improve the ability to recognize the irAEs as early as possible.
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