Checkpoint inhibition and rheumatic events: ‘Many more questions than answers’
It may seem silly to use Whac-A-Mole to illustrate a key challenge in cancer treatment.
But the popular arcade game’s basic premise — use a mallet to knock one mole back into its hole, only to have another pop up a split-second later — is a fitting comparison to the immune-related adverse events that can arise during treatment with checkpoint inhibitors.
Checkpoint inhibition — the foundation of the immunotherapy revolution in oncology — targets checkpoints, or regulators, that inhibit or stimulate the immune system’s actions. Tumors use these checkpoints to protect themselves from immune system attack.
This modality has greatly improved outcomes for patients with advanced malignancies. However, it has been associated with an array of complex autoimmune and systemic inflammatory reactions, including rheumatologic manifestations.
Although it may not be surprising that drugs that boost the immune system can contribute to rheumatologic disorders, these conditions can persist for several years after checkpoint inhibition stops.
“As one would imagine, with their increased use, more patients are going to develop immune-related adverse events (irAEs),” Cassandra Calabrese, DO, rheumatologist in the department of rheumatologic and immunologic disease at Cleveland Clinic, told HemOnc Today. “[Clinicians] must be able to recognize rheumatic irAEs as a complication of checkpoint inhibitors and be aware that many clinical syndromes have been described, including inflammatory arthritis, polymyalgia rheumatica, sicca syndrome, myositis and others. We must do our best to keep up with this quickly growing field, as it has already presented many challenges.”
Seven checkpoint inhibitors — including anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents — are approved in the United States for treatment of several malignancies. These include melanoma or other skin cancers, lung cancer, genitourinary cancers and Hodgkin lymphoma.
Approvals of anti-OX40 and anti-TIM-3 monoclonal antibodies, as well as inhibitors of other immunologic checkpoints, are anticipated in the near future.
This will require greater understanding of the frequency and severity of complications, as well as optimal management strategies, Calabrese said.
Treatment of moderate to severe rheumatologic irAEs often requires use of corticosteroid immunosuppression, as well as interruption or discontinuation of checkpoint inhibitor therapy.
However, rheumatologic irAEs have been reported less consistently than other types.
In some cases, the infrequency of rheumatologic irAEs makes them difficult for oncologists to identify. In other cases, providers’ lack of recognition of musculoskeletal symptoms and the likelihood that these events will not be life-threatening likely contribute to variable reporting.
“We are really just getting a handle on the epidemiology,” Anne R. Bass, MD, professor of clinical medicine at Weill Cornell Medicine, told HemOnc Today. “The problem is that we see these cases, but don’t always know the denominator.”
Richter and colleagues used a database of all patients who received any immune checkpoint inhibitor at Mayo Clinic in Minnesota between Jan. 1, 2011, and March 1, 2018, to assess the prevalence, clinical presentation and management of rheumatologic irAEs.
The study — which many experts consider the first key data set in the field — included 1,293 patients who received a checkpoint inhibitor, 43 (3.3%) of whom were clinically diagnosed with rheumatologic irAEs.
An analysis of those 43 patients, plus another 18 with rheumatologic irAEs who received immune checkpoint inhibitor therapy elsewhere, showed clinical syndromes included inflammatory arthritis (n = 34), myopathy (n = 10) and 17 other rheumatic syndromes.
Most cases of inflammatory arthritis were polyarticular. Twenty-six (76%) of these patients required glucocorticoids, and mean treatment duration was 18 weeks. Five patients (14.7%) received disease-modifying drugs and three (9%) required discontinuation of immune checkpoint inhibitor therapy.
All patients who developed myopathy received glucocorticoids for a mean duration of 15 weeks; two patients died and nine (90%) required permanent immune checkpoint inhibitor discontinuation.
The other rheumatologic syndromes included vasculitis, connective tissue diseases, polymyalgia rheumatica-like syndrome and flared pre-existing rheumatic disease. The majority (71%) of these patients received immunosuppressive therapy and 12% required immune checkpoint inhibitor discontinuation.
Laura C. Cappelli, MD, MHS, assistant professor of medicine at Johns Hopkins School of Medicine, and colleagues systematically reviewed published literature on musculoskeletal and rheumatologic irAEs to improve understanding of their prevalence and clinical characteristics.
They searched the Medline and CENTRAL databases for articles that reported rheumatic and musculoskeletal irAEs secondary to immune checkpoint inhibitor treatment.
Researchers determined arthralgia (prevalence, 7% to 43%) and myalgia (prevalence, 2% to 20%) are commonly reported in this patient population, but there is greater uncertainty regarding the prevalence of other rheumatologic irAEs, including inflammatory arthritis, vasculitis and sicca syndrome.
“We still lack strong epidemiologic data, but rheumatologic irAEs like inflammatory arthritis can be seen in up to 7% of patients treated with certain checkpoint inhibitors,” Cappelli told HemOnc Today. “Other rheumatologic irAEs like myositis occur [among] less than 1% of patients.”
Identification and accurate diagnosis of patients with rheumatologic irAEs — particularly those with arthritis — is an urgent clinical need, Bass said.
“We are just beginning to define these arthritides because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.”
Underlying genetics and environmental exposures may contribute to the heterogeneity in this population, Bass said.
“In our patients, around 20% or 25% present with what looks like rheumatoid arthritis, with both large joints and small joints affected,” she said, noting that only some of them are seropositive. “Another 20% have polymyalgia rheumatica, which causes achy shoulders and hips. Then there is a group who have large joint arthritis — usually the knees, hips, wrists and/or shoulders. We don’t see this pattern of arthritis outside of the immunotherapy context.”
Beyond these manifestations, there are rare reports of psoriatic arthritis, scleroderma and vasculitis.
Myositis is relatively common, whereas dermatomyositis and lupus — diseases that are driven by interferon — are very rare.
Some patients may have a disease susceptibility that is unmasked by immunotherapy, whereas others may have an immunotherapy-specific condition.
“There are just a lot of uncertainties right now,” Bass said.
Bass estimated that 5% of patients treated with checkpoint inhibitors develop arthritis, but approximately 20% experience joint pain.
“Many of these cases are missed by oncologists for two reasons,” Bass said. “[First], they don’t pay as much attention to joint pain as a rheumatologist would, and [second], because steroids used for other adverse events mask joint pain.”
A key concern is that oncologists do not typically recognize the difference between arthritis, arthralgia and polymyalgia syndromes, according to Maria E. Suarez-Almazor, MD, PhD, deputy department chair and distinguished professor in the department of general internal medicine and chief of the section of rheumatology and clinical immunology at The University of Texas MD Anderson Cancer Center.
“Reports vary greatly across trials, possibly because of differences in musculoskeletal adverse events characterizations,” Suarez-Almazor told HemOnc Today. “When we talk about these rheumatic syndromes, there are three primary presentations: arthritis/arthralgia, polymyalgia and myositis.
“Myositis is obviously the scariest, because it is acute and can be life-threatening,” she added. “Admittedly, myositis probably occurs in less than 1% of patients, but we are very concerned about it because patients can also develop myocarditis, a potentially fatal complication.”
Calabrese highlighted another concern.
“What is felt to be weakness from myositis may be the result of progressive intracranial metastasis,” she said.
Key considerations include whether immunotherapy is administered as primary or adjuvant treatment, how a patient responds to oncologic therapy, whether there are alternatives for oncologic treatment, and their life expectancy, Suarez-Almazor said.
“These drugs have not been widely used in patients with limited cancer yet, but that could change,” she said. “Also, new drugs and new combinations will likely come on board, so that will also change the landscape.”
Making the diagnosis
The ability to accurately diagnose rheumatologic irAEs can be challenging, Calabrese said.
“This is a very heterogeneous patient population, with many patients having received chemotherapy, radiation and/or surgery prior to checkpoint inhibitor therapy, and they may have progression of their tumor at the time of evaluation,” she said. “It is important to keep other etiologies on the differential when evaluating a patient for rheumatic irAEs.”
It also is important to note that rheumatologic irAEs described thus far frequently have atypical features compared with de novo disease, Calabrese said.
“For example, they may lack characteristic autoantibodies or require higher doses of prednisone than would be expected,” she said. “Also, unlike all other irAEs to date, rheumatic manifestations appear to be the only irAE with inflammation that persists, even despite discontinuation of the checkpoint inhibitor.”
The potential that rheumatologic irAEs will persist — even for several years after checkpoint inhibitor therapy has been stopped — is a major concern for clinicians.
“We have patients who are 3 years out from receiving immune checkpoint inhibitors who continue to have issues with inflammatory arthritis,” Cappelli said.
Although strides have been made, there is still considerable room for improvement in terms of accurate and timely diagnosis, she added.
“It is still a problem for oncology and other nonrheumatology providers,” Cappelli said. “There is a knowledge gap in the range of rheumatologic irAEs like polymyalgia rheumatica, myositis, vasculitis and inflammatory arthritis.”
Musculoskeletal examination is not taught in depth in all medical training programs, Cappelli said. This makes it difficult for providers to determine if joints are swollen, warm or have a decreased range of motion when evaluating for inflammatory arthritis.
“In the area of myositis, sometimes routine labs will show an elevated aspartate aminotransferase, which can come from muscle in the setting of myositis, but clinicians may go down the path of investigating liver pathology,” she said.
Referral to a rheumatologist at the first sign of any such syndrome is essential, Suarez-Almazor said.
“Not only will a rheumatologist be able to make a diagnosis, but they will be familiar with the medications necessary to treat these patients,” she said. “We have seen that these syndromes are different from other immune-related arthritis in that they sometimes can have an insidious onset and can linger for weeks or months, even after discontinuing immunotherapy.”
A lack of understanding in the clinical community about the potential complications that can arise during treatment of rheumatologic irAEs compounds the challenge of caring for these patients.
“The main challenge in managing patients with rheumatologic irAEs is the lack of evidence-based medicine to guide treatment,” Cappelli said. “IrAEs are a relatively new clinical issue, and more research is needed to determine the most effective and safe treatments. The concern in treating irAEs is that immunosuppression may undermine the tumor immunologic response and have a negative impact on cancer progression.”
For this reason, communication between oncologists and rheumatologists is key.
“Rheumatologists understand better than oncologists how aggressive we can be,” Uma Thanarajasingam, MD, PhD, of Mayo Clinic in Rochester, Minnesota, told HemOnc Today. “[However], any time we go beyond prednisone, we have to partner with oncologists to see how much damage we might be doing to the immune system.
“We have to understand the status of the underlying cancer and whether the patient is responding really well to checkpoint inhibitor therapy, even if they are having a great deal of arthritic pain,” Thanarajasingam added. “Sometimes we have to take a hiatus from the treatment we are using, or switch courses.”
The nature of a particular malignancy and the patient’s prognosis, as well as how immunosuppressive therapy may affect a patient, also must be taken into account, Bass said.
For example, Merkel cell carcinoma is immunologically sensitive and occurs primarily among immune-suppressed individuals. Treating immune-related adverse events experienced by a patient with this malignancy may be much riskier than doing so for a patient who has melanoma.
“You have to understand that the treatment approach for every patient and every tumor is different,” Bass said. “I would love to be able to offer concrete recommendations that always apply. The key is [for oncologists and rheumatologists] to work together ... and [with] the patient to discuss risks and benefits, and to learn from each other.”
A small but growing area of research focuses on specific drug-drug interactions.
During a presentation at Congress of Clinical Rheumatology in 2018, Ami A. Shah, MD, MHS — associate professor of medicine at Johns Hopkins University School of Medicine — said current evidence indicates corticosteroids and short-term tumor necrosis factor inhibitor use may be tolerable without affecting melanoma responses to both the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) and the PD-1 checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb).
“These interactions are still quite an unknown area,” Thanarajasingam said. “We get a sense that certain combinations may have more or less toxicity than others.”
As use of these agents expands into other malignancies, the challenges likely will be compounded, Thanarajasingam said.
“Because these drugs were first approved in melanoma, the toxicities reported in that type of cancer are greatest,” she said. “As usage expands, it will be interesting to see how the toxicity profile changes. For example, lymphoma is a completely different type of cancer, and the immune cells are part of the cancer, so what are the implications for adverse events? It’s still such a new area, so it’s hard to say.”
In 2018, ASCO and National Comprehensive Cancer Network released a clinical practice guideline for management of irAEs among patients receiving checkpoint inhibitor therapy.
A multidisciplinary, multiorganizational panel of experts performed a systematic review of publications on immune checkpoint inhibitor therapy from 2000 through 2017.
The resulting guideline — published in Journal of Clinical Oncology — provided detailed recommendations for organ-specific management of several types of irAEs, including those that affect the skin, nervous system, lungs, musculoskeletal system and cardiovascular system.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” Clifford A. Hudis, MD, FASCO, FACP, CEO of ASCO, said when the guidelines were released. “These new guidelines ... will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
General guidelines for irAEs are as follows:
- Grade 1 — Immune checkpoint inhibitor therapy should be continued with close monitoring for patients, with the exception of those who develop certain neurologic, hematologic or cardiac toxicities.
- Grade 2 — Immune checkpoint inhibition may be suspended and then resumed if symptoms revert to grade 1 or less. In these cases, corticosteroids may be administered.
- Grade 3 — Most cases warrant suspension of immune checkpoint inhibition and initiation of high-dose corticosteroids (prednisone or methyl-prednisolone dosed at 1 mg/kg to 2 mg/kg daily). Corticosteroids should be tapered over a minimum 4 weeks to 6 weeks. Infliximab (Remicade, Janssen) or other immunosuppressive therapy may be required for certain refractory cases.
- Grade 4 — Permanent discontinuation of immune checkpoint inhibitor therapy is recommended, with the exception of endocrinopathies that have been controlled by hormone replacement.
The guideline panel also issued recommendations based on specific rheumatic irAEs, such as inflammatory arthritis, myositis and polymyalgia-like syndrome.
“Despite the often-durable clinical benefits of the immune checkpoint blockade therapy, [immune checkpoint inhibitor] use is associated with a spectrum of adverse effects related to the mechanism of action that is quite different from other systemic therapies, such as cytotoxic chemotherapy,” guideline co-author Julie R. Brahmer, MD, co-director of the upper aerodigestive department within the Bloomberg Kimmel Institute for Cancer Immunotherapy and professor of oncology at Johns Hopkins, and colleagues wrote. “The adverse effects can affect multiple organs of the body ... and there should be a high level of suspicion that any changes are treatment-related.
“The ability to influence immune response even after discontinuation of the immunotherapeutic agent is a unique feature and important education point for patients and their caregivers,” Brahmer and colleagues added. “As such, patients should be encouraged to alert all health care providers that they are receiving or have received an immunotherapeutic agent and to report any changes in health status to each provider.”
The take-home message of ASCO’s guideline is the need for increased awareness and importance of addressing these adverse events promptly.
“[Clinicians] need to understand that there is a place they can turn for information about these events, whether it is the guidelines or other experts who are familiar with them,” Thanarajasingam told HemOnc Today.
This increases the likelihood that basic interventions will be employed early in the course of irAEs, Bass said.
“What I have learned from caring for patients with immunotherapy-induced arthritis is that it often becomes chronic, so it is important to start early with steroid-sparing agents,” she said.
Communication is key
Even with the guidelines in place, much uncertainty remains.
“At this point, there are so many more questions than answers,” Calabrese said. “We have much to learn about risk factors, biomarkers, pathogenesis and optimal treatment of rheumatic irAEs, as well as the impact that treatment for irAEs may have on cancer outcomes.”
Consequently, collaboration between oncologists and rheumatologists is essential.
“Communication is the most important thing to successfully care for patients with rheumatologic irAEs,” Cappelli said. “The oncologist and rheumatologist must reach consensus about ways to manage each patient.
“We contact the patient’s oncologist on the day of their clinic visit to us so we can confirm the plan,” she said. “It is also important for the patient to be aware of the role each physician plays in their care. Often patients ask us about plans for their cancer therapy and we need to remind them that their oncologist will guide their cancer treatment and we will manage their side effects, in collaboration with their oncologist.”
A cautious approach is appropriate, Calabrese said.
“If there are symptoms of grade 2 or higher based on [Common Terminology Criteria for Adverse Events] grading, they should be referred to a rheumatologist,” she said. “Long-term management of these patients requires multidisciplinary care that addresses the patients’ rheumatic manifestations while at the same time treating their cancer.”
The multidisciplinary care may need to extend beyond oncologists and rheumatologists, Suarez-Almazor said.
“We need to promptly recognize when others need to be involved — for instance cardiologists when suspecting myocarditis,” she said. “The benefits and harms of therapies need to be understood quickly, along with how the various therapies are interacting with each other.”
Despite the challenges associated with diagnosing and treating rheumatologic irAEs, many in the field consider it an opportunity to improve the knowledge base and ultimately improve outcomes.
“We have to take every opportunity to learn, because we are going to see more and more of these patients,” Bass said. “It is critical that we have people who understand and can manage these patients and the problems they confront.
“In most cases of rheumatoid arthritis, the development of antibodies to disease onset can usually be 3 to 5 years,” she added. “[Among patients who receive immunotherapy], we are seeing arthritis develop within 3 to 4 months of starting treatment. This means we can study this disease and biomarkers over a shorter period of time, and they will likely teach us something about rheumatic diseases that we see in other contexts.”
It also is important for members of the oncology care team to have mechanisms in place to identify and manage these rapidly developing conditions, Suarez-Almazor said.
“Many of these are patients who cannot wait to be seen by a rheumatologist for weeks or months, as decisions about their cancer treatment are critical,” she said. – by Rob Volansky
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Kapiteijn E. Abstract SP0097. Presented at: EULAR Annual Congress; June 13-16, 2018; Amsterdam.
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Richter MD, et al. Arthritis Rheumatol. 2018;doi:10.1002/art.40745.
Shah A. Cancer, immunotherapy and autoimmune syndromes: Rheumatic consequences of checkpoint inhibitors; Presented at: Congress of Clinical Rheumatology; May 17-20, 2018; Destin, Fla.
For more information:
Anne R. Bass, MD, can be reached at Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021; email: firstname.lastname@example.org.
Cassandra Calabrese, DO, can be reached at Cleveland Clinic, 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: email@example.com.
Laura C. Cappelli, MD, MHS, can be reached at Johns Hopkins Medicine, 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD 21224; email: firstname.lastname@example.org.
Maria E. Suarez-Almazor, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. #437, Houston, TX 77030; email: email@example.com.
Uma Thanarajasingam, MD, PhD, can be reached at Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: firstname.lastname@example.org.
Disclosures: Cappelli reports research funding from Bristol-Myers Squibb, as well as consultant roles with Regeneron and Sanofi. Bass, Calabrese, Suarez-Almazor and Thanarajasingam report no relevant financial disclosures.