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Although treatment with immune checkpoint inhibitors (ICIs) is associated with better survival in many cancer settings, these therapeutics can induce immune-related adverse events (IrAEs).1 ,2 REISAMICi is a French, prospective, multicentre, academic registry sponsored by the Gustave Roussy Institute cancer centre. The objective is to better detect, document and manage IrAEs.
Connective tissue diseases (CTD) have not previously been reported in patients treated with anti-PD1/PDL-1 agents. The REISAMIC registry was screened for reports of CTD.
Of the 447 patients supervised in the REISAMIC registry, three have developed CTD: two cases of Sjögren's syndrome and one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren's syndrome (table 1). A case of ANA+ myositis registered in REISAMIC by another investigating centre was also included in the study. The mean patient age was 62 years. Three of the patients were female. All had metastatic cancer. Two had received anti-PD1 agents and two anti-PDL-1 agents. None of the patients had apparent symptoms of CTD prior to the initiation of the ICI. The mean (range) time interval between the first ICI infusion and the first symptom of CTD was 60 days (24–72). The mean (range) time interval between the first symptom and diagnosis of the CTD was 40 days (10–74). The ICI was discontinued in three patients. Two of the patients were treated with steroids (1 mg/kg/d).
We looked for ANAs in serum samples that had been collected prior to initiation of the ICI. All three tested patients were positive for ANAs, and two patients had anti-SSA (despite the lack of any clinical symptoms suggestive of Sjögren's syndrome).
Our study (based on a large, dedicated academic registry) is the first to have observed CTD in patients treated with anti-PD1/anti-PDL-1 agents. The high proportion of cases of Sjögren's syndrome is noteworthy. Two patients fulfilled the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren's syndrome and a third one with cryoglobulinemia and anti-SSA did not benefit from lip biopsy or from dryness measurement. Sicca symptoms and arthritis were recently described in patients treated with ICIs but without anti-SSA/SSB antibodies.3 The withdrawal of ICI therapy in three of the four patients and the requirement for long-term prednisone treatment emphasise the potential severity of these IrAEs.
One of the strengths of our study is the estimated prevalence of CTD: 0.7% in the REISAMIC registry. One limitation relates to the possibility that some patients with milder symptoms might not have been investigated by their oncologist. Conversely, one patient received nivolumab associated with ipilimumab, a combination of ICIs, which is known to increase the risk of IrAEs.
Flare-ups of pre-existing active rheumatic diseases in patients treated with anti-PD1 agents have been reported recently.4 Our findings raise the question of screening for asymptomatic patients at risk of IrAEs (eg, by recording their full medical history and testing for ANAs). At-risk patients should be closely monitored during their immunotherapy.
While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care. This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.5 ,6
Contributors OL, the corresponding author, states that all the authors listed have contributed to the work.
Funding LA: research funding: Novartis, Pfizer.
Competing interests Honoraria: SC for Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme and Roche. LA for Novartis, Pfizer, BMS, Sanofi and Ipsen. OL for Merck Sharp Dohme and Genzyme.
Ethics approval Gustave Roussy ethical committee.
Provenance and peer review Not commissioned; externally peer reviewed.
↵i Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie.