Oncologists, rheumatologists, internists, family medicine specialists
The goal of this study was to determine the long-term outcomes of cancer patients treated with immune checkpoint inhibitors (ICIs) who developed inflammatory arthritis.
Question Addressed:
- What factors were associated with ICI-induced inflammatory arthritis persistence after treatment cessation?
In cancer patients who developed arthritis during treatment with ICIs, joint symptoms were less likely to resolve in those with greater exposure to these drugs and in those treated with a combination of ICIs, a prospective observational study found.
Action Points
- In cancer patients who developed inflammatory arthritis during treatment with immune checkpoint inhibitors (ICIs), joint symptoms were less likely to resolve in those with greater exposure to these drugs, those treated with a combination of ICIs, and those with a history of other immune-related adverse events, according to a prospective observational study.
- Understand that ICI-induced inflammatory arthritis can become a chronic condition in cancer patients, warranting close monitoring for joint-related symptoms, early referral to and close follow-up by rheumatologists, and potentially more aggressive immunosuppressive treatments.
In a multivariate analysis, the likelihood of improvement in inflammatory arthritis was lower for patients with longer duration of ICI treatment, with a hazard ratio of 0.82 (95% CI 0.73-0.92, P=0.001), and for those on combination ICI regimens (HR 0.06, 95% CI 0.01-0.50, P=0.009), researchers reported online in Annals of the Rheumatic Diseases.
“This information provides insight into which individuals are at highest risk for developing persistent inflammatory arthritis, thus warranting close monitoring for joint-related symptoms, early referral to and close follow-up by rheumatology, and potentially more aggressive immunosuppressive therapy,” Cappelli’s group wrote.
As ICIs are increasingly used in treating a range of cancer types, researchers have seen the development of a number of inflammatory and autoimmune syndromes in patients during treatment, possibly through activation of T cells against antigens to the self, the researchers said. Some of these adverse events, such as pneumonitis and colitis, can be deadly, while others, such as inflammatory arthritis and thyroid dysfunction, can have profound and ongoing impact on patients’ function and quality of life. There have also been reports of the rapid appearance of erosions in affected patients.
Most patients who develop arthritis have required treatment with corticosteroids, other immunosuppressives, and even biologic agents, but it has been challenging to develop optimal strategies, given the context that their cancer treatment has involved immune activation. In addition, risk factors for the occurrence and persistence of arthritis have so far been unknown.
For this study, the researchers looked at the long-term outcomes of 60 patients who developed arthritis with ICI treatment. The team recruited patients from 2015 to 2018 who had been referred to the Johns Hopkins Arthritis Center and who had been given an anti-CTLA-4, anti-PD-1, or anti-PD-L1 agent, or a combination of these drugs. The average follow-up time was 12 months after stopping the ICI treatment.
Slightly more than half of the participants were women; mean age was 59 and most were white. The median Clinical Disease Activity Index at the time of recruitment was 17.5, which represents moderate activity. Duration of ICI treatment averaged 7 months, and half of patients had reported other immune-related events, most often colitis and rash.
The most common types of cancer treated in this population were melanoma and non-small cell lung cancer, and treatment outcomes included stable disease in 28.3% of patients, progressive disease in 25%, complete response in 23.3%, partial response in 16.7%, and no evidence of disease in 6.7%.
Follow-up data 3 months after cessation of ICI treatment were available for 51 patients, at which time 70.6% still had active arthritis. Among the 41 for whom 6-month data were available, 48.8% had persistent arthritis, and among the 20 patients who continued to have inflammatory arthritis at 6 months, 14 remained symptomatic during additional follow-up.
In a univariate analysis, factors associated with a decreased likelihood of improvements in arthritis were:
- Longer duration of ICI treatment: HR 0.93 (95% CI 0.87-0.99, P=0.02)
- Combination therapy: HR 0.29 (95% CI 0.12-0.72, P=0.008)
- History of other immune-related events: HR 0.61 (95% CI 0.39-0.95, P=0.03)
Three-quarters of patients were prescribed immunomodulatory treatment for their arthritis: corticosteroids in 48, conventional disease-modifying antirheumatic drugs (DMARDs) in 19, and biologics in 11.
Among the 24 patients who received either DMARDs or biologics, only four (16.7%) experienced cancer progression, which did not differ significantly from the rates of progression in patients not given these drugs (22.2%, OR 0.65, 95% CI 0.17-2.47).
A limitation of the study was the possibility of selection bias, acknowledged the researchers.
Source Reference: Annals of the Rheumatic Diseases 2019; DOI: 10.1136/annrheumdis-2019-216109
Study Highlights and Explanation of Findings:
This study confirms earlier smaller studies that indicated that inflammatory arthritis can remain active for months to years after treatment with ICIs ends. The authors noted that other immune-related adverse events that may occur or reoccur and become chronic after ICI cessation are pneumonitis, colitis, hepatitis, dermatitis, and neuropathy.
Previous studies of other types of immune-related adverse events have suggested that most develop during treatment induction, which does not appear to be the case with arthritis, the researchers said. “The kinetics of ICI-induced inflammatory arthritis development differs from many other immune-related adverse events, and may suggest unique immune pathogenesis for ICI-induced inflammatory arthritis, potentially due to longer exposure to ICI therapy.”
“Delayed initial presentation of [immune-related adverse events], with symptoms starting even after ICI cessation, is a related concept that is being increasingly recognized,” the authors wrote. “Further prospective cohort studies are needed to determine which [immune-related adverse events] besides [inflammatory arthritis] are likely to persist or present after ICI cessation.”
They added that the types of immune-related adverse events that persist “may indicate how the immune system interacts with particular target tissue microenvironments causing a feed forward loop of autoimmunity that becomes independent of ICIs.”
The researchers noted that like endocrine-related immune-related adverse events, ICI-induced inflammatory arthritis may need chronic treatment. The cited concern with using immunosuppression to treat these adverse events has been that they may negatively affect antitumor immune responses. Importantly, this study and a number of previous trials indicated that DMARDs and TNF inhibitors used to treat immune-related adverse events do not in fact affect antitumor responses.
Interestingly, the data suggest that patients who develop persistent arthritis may experience better antitumor responses compared with those who have transient arthritis. “Other studies have demonstrated that development of [immune-related adverse events] associates with better progression-free and overall survival, but persistence of an [immune-related adverse event] has not been examined,” the researchers wrote.
Further exploration of the biology of the various types of immune-related adverse events may help in determining more closely targeted therapeutic strategies for these conditions, they noted. “Overall, continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced inflammatory arthritis.”
Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College
Primary Source
Annals of the Rheumatic Diseases
Secondary Source
MedPage Today
Source Reference: Walsh N “ICI-Linked Arthritis: Risks for Persistence” 2019.
https://www.medpagetoday.org/rheumatology/arthritis/82546?_ga=2.252979721.1081251847.1570409347-265074527.1569866268
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