Rheumatology, oncology teamwork crucial to assess checkpoint inhibitor 'risks, benefits'
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Collaboration between oncologists and rheumatologists is essential to curtail the increasing prevalence immune-related adverse events linked to checkpoint inhibitor therapy, according to a presenter here.
“This is an increasingly important issue for rheumatologists,” Laura C. Cappelli, MD, MHS, MS, assistant professor of medicine in the division of rheumatology at Johns Hopkins University School of Medicine, told attendees.
Immune checkpoint inhibitors (ICI) have become the most commonly used drugs by oncologists. There are seven FDA-approved drugs for a “wide variety of indications,” Cappelli said.
The two general classes of drugs used for checkpoint inhibition include PD-1/PD-L1 blockade and CTLA-4 blockade. “They have a relatively non-specific mechanism of action,” Cappelli said.
There are a few ideas about why each drug class leads to immune-related adverse events (irAEs). CTLA-4 Blockade lowers the threshold for expansion of activated T cells and kills T-reg cells, while PD-1/PD-L1 blockade activates exhausted T cells and blocks inhibitory effects of dendritic and natural killer (NK) cells. But Cappelli stressed that there is still much to be learned about these exact mechanisms. “Like all of immunology, it is complicated,” she said.
While incidence rates are still coming into focus, Cappelli suggested that as many as 56% of patients taking combination therapy with the two checkpoint approaches may experience an irAE.
There is also uncertainty surrounding the timing of irAE development, according to Cappelli. “It can occur at almost any time of immune checkpoint inhibitor treatment,” she said.
A range of severity has also been observed. For example, some forms of thyroid dysfunction are asymptomatic or pauci-symptomatic. Also, mild forms of dermatitis do not significantly impact patients.
Conversely, outcomes like myocarditis or encephalitis may occur and be fatal for some patients. “There really is a spectrum of how these patients can get affected by these immune related events,” Cappelli said.
Cappelli also addressed the extent to which irAEs are similar and different from rheumatologic and autoimmune diseases. ICI-associated inflammatory arthritis can have a “heterogeneous presentation” depending on the tumor type. “The joints involved can vary from the large joints to the small joints,” she said. “We see synovitis, but we also see dactylitis and enthesitis.”
Some patients may have typical inflammatory markers like rheumatoid factor (RF) and citrullinated peptide (CCP), but many do not.
Treatment of ICI arthritis depends on the severity of the event, according to Cappelli. NSAIDs may be used in mild cases, while corticosteroids or even biologics are used in more severe patients. “It also depends on the [ICI] used and oncology preference because we do not have any clinical trials to guide us,” she said.
Another condition that should be on the radar for patients being treated with ICIs include dry mouth and dry eyes from a Sicca-like syndrome. “The onset of this can be acute and quite severe,” Cappelli said.
Treatment paradigms for these events should mimic those used for similar manifestations in Sjögren’s syndrome, according to Cappelli. In addition to saliva substitutions or prednisone, referral to a dentist or ophthalmologist may be necessary.
Polymyalgia rheumatica (PMR) and giant cell arteritis have also been reported in the ICI setting, according to Cappelli. She noted that presentation of these syndromes is “sometimes typical, sometimes not.”
Experts are also still learning about incidence rates of other forms of vasculitis in ICI. “We do not know much about frequency or type,” she said.
Of particular concern for rheumatologists is myositis in patients treated with ICIs. “It is the most morbid thing rheumatologists are likely to see,” Cappelli said, noting that distal and diaphragmatic weakness may be present. These syndromes may also overlap with myocarditis or myasthenia gravis, which are associated with high mortality.
Other syndromes that occur less frequently but should be on the radar of rheumatologists include eosinophilic fasciitis, subacute cutaneous lupus and a sarcoidosis-like reaction, according to Cappelli.
As experts continue to learn about all of these syndromes, Cappelli urged ongoing communication between rheumatology, oncology and patients. “Hopefully, we will soon have better understanding of the risks and benefits of using checkpoint inhibitors,” she said.
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Cappelli LC. Autoimmune Effects of Checkpoint Inhibitors: Are they Safe in Patients with Pre- Existing Rheumatologic Disease? Presented at: Congress of Clinical Rheumatology-East annual symposium; August 12-15, 2021 (hybrid meeting).
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