More Questions Than Answers: Dealing With Rheumatic Complications of Immunomodulators

Immune checkpoint inhibitors have been in heavy use in major cancer centers for more than a decade. These drugs are now used for several malignancies. It has been established, somewhat anecdotally, that these are associated with myiad rheumatic complications. While larger, more comprehensive and more rigorous data sets are beginning to emerge, questions remain.

Laura Cappelli, MD, MHS, instructor of Medicine in the Division of Rheumatology at the Johns Hopkins School of Medicine, laid out the fundamentals.

“Patients treated with immune checkpoint inhibitors can develop rheumatic symptoms at various times in their treatment course,” she said. “These symptoms can occur within weeks of starting or can begin over a year after initiation of immune checkpoint inhibitors. Even if patients have discontinued immune checkpoint inhibitors, symptoms can persist. It is important to obtain a complete history of cancer treatment for patients with malignancies.”

Immunotherapy is a broad term for any cancer therapy that activates the immune system, according to Cappelli. “We have focused on immune checkpoint inhibitors targeting CTALA-4, PD-1 and PD-L1, as these are targets of FDA-approved medications, but there are other agents under investigation targeting related immune pathways that may lead to rheumatic complications,” she said. “Theoretically, any therapy that activates the immune system to fight cancer could lead to rheumatic complications related to that immune activation, so rheumatologists should keep this in mind when seeing patients on any type of immunotherapy.”

Padmanee Sharma, MD, PhD, scientific director of the Immunotherapy Platform, professor in the Departments of Genitourinary Medical Oncology and Immunology, and codirector of the Parker Institute for Cancer Immunotherapy at The University of Texas MD Anderson Cancer Center, commented from the oncology side.

“We are aware that immune checkpoint agents have these rheumatic side effects,” she said. “We have seen the joint pain and how it manifests, and we understand that we need to initiate steroids to improve the symptoms.”

There are still questions from the oncology community. “In terms of rheumatic disease, [rheumatoid arthritis] RA or lupus, people are not sure that it is autoimmune diseases that are being generated,” Sharma said. “No one is seeing the same autoantibody panel that would lead you to say that is the condition in patients who are receiving immune checkpoint inhibitors. There is a diverse array of symptoms.”

Sharma suggested encouraging patients to “tell their story a little better” could be useful in better understanding this population. But this might only carry the ball so far. Hard data involving hundreds or thousands of patients may begin to answer the questions surrounding this phenomenon. Before these studies can be conducted, it is necessary to more clearly define the questions.

Dealing With Unknowns

Cassandra M. Calabrese, DO, the first fellow doing a newly established combined fellowship in both rheumatology and infectious diseases at the Cleveland Clinic, is now focusing much of her research in this area and described the experience of dealing with this patient population as “humbling.” Questions remain about the pathophysiology of these complications, about biomarkers and risk factors, about how to optimally treat these and about the ramifications of treatment on their underlying malignancy.

“We know so little about these rheumatic-related adverse events,” she said. “We do not have a clear picture of incidence rates. There is no standard reporting mechanism. Or, to be more specific, there is a lot of variation in reporting.”

Calabrese and colleagues developed a system to assess immune-related adverse events in a cohort of 12 patients with cancer who underwent therapy with checkpoint inhibitors. Pre-existing RA was reported in two patients, while one had pre-existing psoriatic arthritis (PsA). The analysis included nine patients without pre-exisiting autoimmune disease; five patients with melanoma; two patients with lung cancer and two patients with renal cell carcinoma. Rheumatic adverse events were reported in 11 patients. There were four cases of inflammatory arthritis, two cases of polymyalgia rheumatica-like symptoms, five cases of sicca and one case of myositis, according to the results. The average time to onset of these events was 52 days after starting immunotherapy. Glucocorticoid therapy in all patients and additional therapy in three patients yielded significant improvement in five members of the cohort and moderate improvement in three. Flares occurred in two of three patients with underlying autoimmune disease. Researchers concluded, however, that much remains unknown about rheumatic complications in this population.

“We are still in the early stages of diagnosing and treating rheumatic immune-related adverse events secondary to checkpoint inhibitors and many questions remain unanswered,” Calabrese told Healio Rheumatology. “Given the proliferation of checkpoint inhibitor therapy and the imminent arrival of immunotherapies targeting other immunologic checkpoints, rheumatologists must be alerted to these complications and collaborate with treating oncologists for accurate diagnosis and management.”

“The most important thing we can take away from this study, beyond the data, is that it increased our experience and knowledge in this area of rheumatologic complications of checkpoint inhibitors,” Calabrese said. “We had previously been limited to case reports and small series.”

The data set from Calabrese was the largest that examined this patient population until a study from Cappelli and colleagues. They performed a systematic review of 51 studies that included 33 clinical trials. All analyses included findings on rheumatic and musculoskeletal adverse events treated with PD-1, PD-L1 or CTLA-4 inhibitors. Findings from the clinical trials indicated a broad range of arthralgia incidence (from 1% to 43%). A similarly wide range — 2% to 20% — was reported for myalgia, while arthritis occurred in 1% to 7% of the population and vasculitis ranged from 2% to 3%. Results of one observational study indicated an arthritis incidence of 2% among patients treated with ipilimumab (Yervoy, Bristol-Myers Squibb) for renal cell carcinoma or melanoma. Case series results showed lupus, vasculitis, inflammatory arthritis, inflammatory myopathy and eosinophilic fasciitis incidences. The researchers concluded that while arthralgia and myalgia incidence may be common in patients treated with these drugs, the true incidence of all rheumatic complications remains uncertain.

“These conditions are described in case reports and series, but there are no prospective studies in the current literature to guide [the] evaluation and treatment of patients with rheumatic and musculoskeletal sequelae from immune checkpoint inhibitors,” Cappelli told Healio Rheumatology.

Focus on What is Known

As for other takeaways from the findings, Calabrese said that although many of the immune-related adverse events might look like RA or polymyalgia, or present similarly as those rheumatic diseases, they do not act like these diseases in terms of serology or positive antibodies.

“They also do not respond to treatment the same way,” Calabrese said. “They require much more intense immunosuppression, much higher doses of steroids, than patients with rheumatic diseases unrelated to a checkpoint inhibitor.”

Cappelli echoed this point. “Clinically, features of immune-related adverse events from checkpoint inhibitors can differ from classical rheumatic diseases,” she said. “The patients with sicca syndrome tend to have more severe dry mouth than dry eyes, which is different than some patients with primary Sjögren’s syndrome. Patients with inflammatory arthritis can have a rapidly additive course where one joint is affected first, followed quickly by involvement of many other joints.”

Another key difference between traditional rheumatic disease patients and this group is in the theoretical risks of immunosuppression in patients with active malignancy or recent remission, Sharma added. “Any treatment decisions are made only after discussion with the referring oncologist and the patient about potential risks and benefits of immunosuppression in the setting of cancer,” she said.

Noha Abdel-Wahab, MD, PhD, postdoctoral fellow in the Section of Rheumatology and Clinical Immunology at the University of Texas MD Anderson Cancer Center in Houston and lecturer and consultant of Rheumatology in the Department of Rheumatology and Rehabilitation at Assiut University Hospitals in Egypt, described some patterns in her experience with this patient population.

“These manifestations include, among others, non-specific rash, vitiligo, psoriasis, arthralgia, arthritis, myalgia, myositis, endocrine manifestations, colitis, neurological syndromes and, on occasion, what appears as de novo disease, for instance, lupus,” she said. “These adverse events tend to present acutely, with severe symptoms, and evidence of a high inflammatory status, with elevated markers. From a diagnostic perspective, laboratory and imaging studies may be required to determine the extent and severity of the adverse event, and whether these manifestations represent an underlying rheumatic disease. In general, many of the commonly encountered serological autoantibodies typical of various rheumatic conditions are absent in patients with immune-related adverse events.”

This leads to what Calabrese believes is the most important take-home from her data set. “Rheumatologists need to be aware of this entity,” she said. “We have to make sure to consider the etiologies, timing of onset, and determine the role of checkpoint inhibitors.”

Communication

With only a few data sets to draw from, communication between rheumatology and oncology is of critical importance. “I do not think everyone in the rheumatology community is even aware of this yet,” Calabrese said. “As for my thoughts for the oncology side, I would also just suggest that they be aware of this potential complication and refer these patients as soon as possible. Awareness is critical.”

Abdel-Wahab built on this point. “At this time, there are no clear recommendations, and therefore, clinicians need to weigh carefully with the patient the benefits and risks of treatment,” she said. “This decision requires a multidisciplinary approach, with an evaluation of cancer prognosis and alternative effective therapies beyond checkpoint inhibition, the severity of the underlying rheumatic disease, and the patient’s preferences and tolerance for different risks.”

Speaking from the oncology side, Elizabeth I. Buchbinder, MD, physician at the Dana-Farber Cancer Institute, said a better understanding of when to treat these patients would be useful.

“Of course, we are treating the pain, but what about limiting long-term complications by treating sooner rather than just treating with steroids?” she said. “Help with understanding those details would be incredible. We still need to know what we should be looking out for.”

Another knowledge gap pertains to the methods of treating these patients with minimal impact on the immune system, according to Buchbinder.

“Some treatments are better at controlling joint inflammation, but have less impact on T cells,” she said. “We need to know the least amount of therapy we can use to cure the rheumatic complication, but not impact the effect on the cancer treatment.”

For Sharma, at MD Anderson, there are fewer questions. “We treat so many patients with immune checkpoint inhibitors,” she said. “We have conducted over 100 clinical trials with these drugs and have been using them for the last 10 [years] to 15 years.”

An added benefit at MD Anderson is the in-house rheumatology department. Regular meetings between experts in the two fields keep all clinicians informed. She acknowledges, though, that even with this ideal situation, there are gaps in knowledge about checkpoint inhibitors, particularly surrounding the mechanism of action. “These agents are driving an inflammatory immune response which leads to the adverse event of rheumatic symptoms,” she said. “We get the impression that some rheumatologists who see these patients are dealing with a typical osteoarthritis patient, and not seeing it as a manifestation of a drug that is being used to treat their cancer.”

A critical question is when to hold therapy to control the patient’s rheumatic symptoms. “Clinicians in both specialties need to see how patients respond and pay attention to their symptoms,” Sharma said.

Cappelli spoke directly to oncology. “First, we would encourage oncology providers to screen their patients for development of symptoms of arthritis, sicca syndrome and other rheumatic diseases while they are on immune checkpoint inhibitors,” she said. “Since rheumatic immune-related adverse events are not life-threatening, they may be under recognized. Also, the arthritis and sicca syndrome can persist after immune checkpoint inhibitors are stopped. Rheumatologists are happy to work with oncologists in the longitudinal care of their patients.”

After awareness comes treatment, according to Calabrese. “It is a big challenge to immunosuppress a patient who is in cancer remission,” she said. “We understand that this could be counterproductive to their cancer therapy.”

Calabrese spoke of specific treatments. “There are no data for tocilizumab yet,” she said. “People ask why we do not use methotrexate more often. The reason for us is that [disease-modifying antirheumatic drugs] DMARDs require 2 [months] to 3 months of treatment to have a benefit. But these patients have symptoms here and now that need attention right away. We need to make sure we are in touch with oncologists to manage treatment. Early referral is key.”

In the Community

While communication between specialties is largely optimized in major centers, oncologists and rheumatologists in community centers further afield are in a different position.

“It is not uncommon for us to see a patient and recommend immune therapy, and they go receive the treatment locally,” Buchbinder said. “Then I get a call from the patient months later about a rheumatic complication. Their doctor has told them not to worry, but we would have treated it because it is an immune-related toxicity.”

Buchbinder acknowledged, however, that this situation is improving. “There have been efforts to educate physicians in the community,” she said. “That same gap knowledge existed when we started, so I think there are still things that are not being recognized. But, as time goes on and people realize these medications are here to stay, these events will be more recognizable, and patients will be treated more appropriately.”

Sharma also agreed community physicians face challenges, particularly in patients with stage 4 cancer, but she said her rheumatology colleagues at MD Anderson reach out to the community and participate in long-term follow-up. “I do not necessarily reach out to rheumatologists, but we on the oncology side reach out to local oncologists,” she said. “We can help them understand the treatments.”

An important question is when to refer patients to rheumatology from oncology.

“Referral patterns should be based on symptoms, how they are impacting quality of life and how the patient responds to steroids. If they respond, there is not a rush to refer. If they do not do well, or if there are accompanying symptoms [that] add more complications, we refer,” Buchbinder said.

Lack of Guidelines

There are currently no guidelines to deal with this patient population, according to Buchbinder. “Guidelines on this would be amazing,” she said. “But we have to be careful because we do not want to flood our rheumatology group with every patient who has a joint ache, so the guidelines will have to be specific about warning signs, who should be referred and when, other treatment options beyond low-dose steroids that we may not be considering and the use of methotrexate.”

Guidelines could begin with more rigorous reporting, according to Abdel-Wahab.

“Rheumatic adverse events are generally underreported in oncology clinical trials with no detailed description of the clinical, laboratory and imaging data,” she said. “The Oncologic Common Terminology Criteria for Adverse Events used in these trials does not characterize well the myriad of rheumatic manifestations that can occur in patients developing immune-related adverse events. Most often, only grade 3 or higher toxicity is reported, and rheumatic manifestations are not perceived as severe.”

Buchbinder raised questions about whether other agents should be used sooner to avoid overuse of steroids, and suggested that issues like this might be resolved with a formal set of recommendations.

“One thing we need and we are finally getting it is interest from the other end,” she said. “It did not happen when immune therapies were used in melanoma, but now we are getting interest from rheumatology because immune checkpoint inhibitors are being used for lung cancer and other malignancies. Whenever there is this much interest, it helps.”

Calabrese described the grading system used by oncologists at her institution. “There is one for gastrointestinal side effects, one for dermatologic effects, and so on” she said. “If it is grade 1, do this; grade 2, do that. But this system does not exist for rheumatic complications. Some patients do not have severe enough complications to warrant it, so they might not be identified as someone that requires attention. These events can present in various different ways, and people have different ways of reporting them. But I think in the near future, it could be feasible for us to have a grading system for rheumatic complications.”

Abdel-Wahab offered some clinical solutions. “For mild events, such as rash, topical corticosteroids may be adequate and drug discontinuation is not required,” she said. “Oligoarthritis can be treated with intra-articular corticosteroids. Many immune-related adverse events, including arthritis, can be severe and present acutely, requiring rapid-acting agents, such as corticosteroids in high doses which should be initiated immediately. According to the severity of the symptoms, intravenous administration may be required, and more aggressive immunosuppressive therapy, especially if they have other concomitant adverse events.”

Infliximab has been used to some efficacy, particularly in patients with colitis, according to Abdel-Wahab. “Most patients with severe immune-related adverse events will require permanent discontinuation of checkpoint blockade therapy,” she said. “In our experience in patients with arthritis, therapy re-challenge often results in a flare, although this can be mitigated by concomitant treatment with corticosteroids or immunosuppressants, notwithstanding that the effect of these treatments on tumoral response to checkpoint inhibition is uncertain.”

Healio Rheumatology asked Sharma about the role of professional societies in developing recommendations. “Their role is in education,” she said. “We have to be better at educating the entire community. We have to educate the local community doctors, as well as patients. Patients need to recognize these symptoms earlier, report them earlier, get treated earlier.”

Sharma added databases for recording information on these patients also will help in the research arena. “This will lead to a larger group of patients we can study for what potential mechanisms may be at work,” she said. “We need to pool our resources.”

More Emerging Data

Clinical trials in both rheumatology and oncology that test some of these interventions would also be useful, according to Buchbinder. Apart from the Calabrese and Cappelli studies, more data sets were presented at the most recent American College of Rheumatology Annual Meeting.

Pinkston and colleagues aimed to identify the type and frequency of immune-related adverse events in patients receiving immune checkpoint inhibitors. They analyzed adverse events in 74 patients treated for melanoma with pembrolizumab at the Mayo Clinic in Jacksonville during a recent 2-year period. Events were grouped by organ system. There were 69 cases of advanced melanoma treated with at least one cycle of the drug. Three patients consulted a rheumatologist. The researchers evaluated notes from the initial assessment in oncology, along with follow-up notes, hospitalization and referral records and history of treatment with glucocorticoids. In one patient, recurrent diarrhea was reported, along with a diagnosed case of large-vessel vasculitis detected via CT scan. In this patient, thickening of the abdominal aorta and ileum and ileal dilation were observed, which suggested ischemia due to vasculitis of the superior mesenteric artery, according to the researchers.

A history of Raynaud’s disease was reported in another patient. Hand pain with swelling occurred in this individual. Despite treatment with prednisone before evaluation, swelling and limited bilateral extension of the wrists remained.

Another patient with a history of seronegative rheumatoid arthritis was in remission. This patient no longer required hydroxychloroquine and did not experience flare-ups during pembrolizumab therapy.

Among 34 patients with musculoskeletal and connective tissue events, 28 reported arthralgia and 11 underwent glucocorticoid therapy. There were also 26 patients with skin and subcutaneous tissue events. Pruritus was reported in 22 of these patients, while five received glucocorticoids. Gastrointestinal events occurred in 25 patients. Twelve of these patients had diarrhea, while nine patients received glucocorticoids. Among 13 patients with endocrine events, 12 patients experienced hypothyroidism and one experienced hypophysitis.

“We are trying to understand differences between tumor rejection and a sideeffect profile,” Buchbinder said. “We are trying to understand the antigens involved in cancer cells and normal cell tissue that creates side effects. Do I think we will be able to completely uncouple anti-tumor effects from side effects? Probably not. But we will be able to see the side effects coming down the line. We will learn how to recognize these effects sooner.”

Abdel-Wahab and colleagues systematically reviewed 45 cases of patients with cancer and autoimmune disease before being assigned checkpoint inhibitor therapy. The findings from 14 studies included patient characteristics, checkpoint inhibitor type, immune-related adverse events, overall management, clinical outcome and the presence or absence of re-treatment. Concomitant treatment for autoimmune disease with corticosteroids, DMARDs and biologics was reported in 86.8% of the cohort. At checkpoint inhibitor therapy initiation, 53.9% of the patients had an active autoimmune disease. Ipilimumab was used in 88.9% of these patients. Forty percent of the cohort experienced novel immune-related adverse events after treatment. Exacerbation of a pre-existing autoimmune disorder was reported in 28.9% of the group, while 8.9% reported novel events and exacerbation of an existing disorder and 40% experienced no adverse events. Hypophysitis and colitis occurred in most patients, with novel immune-related adverse events (27.8% each).

In 33.3%, physicians recommended discontinuation of therapy. One fatality from toxic epidermal necrolysis was reported, along with a death due to severe colitis. Re-treatment with checkpoint inhibitor therapy was reported in one patient with ulcerative colitis who had initial exacerbation of his colitis associated with ipilimumab. Upon re-treatment, grade 3 anterior panhypopitutarism and tracheobronchitis subsequently manifested as novel immune-related adverse events in this patient.

“We need longitudinal evaluation of patients to determine the clinical risk factors for developing rheumatic immune-related adverse events and biomarkers of these events,” Cappelli said. “Evaluating how the immune response changes from before to after immune checkpoint inhibitor therapy in those who develop rheumatic events vs. those who do not will be informative as to why these events develop.”

Moving Forward

For Calabrese, prioritizing patients is critical. “From a pathology standpoint, the sooner we can identify them, the better,” she said. “Get them in the lab. A set of labs ordered on the oncology side would be useful. This could involve what should be checked before they start on checkpoint inhibitors, their cytokine profiles. But this is all speculative right now.”

For Abdel-Wahab, it is also important to determine what other factors may influence the development of these events in cancer patients without prior inflammatory conditions. “We know that many patients can receive therapy for months without ever developing adverse events, so the effect is not always cumulative,” she said. “Genetic factors, other comorbidities, and possibly the patient’s microbiota may play a role in the development of specific toxicities. Finally, there is limited knowledge as to whether the immunosuppression used to treat these events may blunt the beneficial antitumor immune responses stimulated by checkpoint blockade. Studies evaluating the effect of aggressively treating immune-related adverse events with different agents are needed to develop adequate recommendations for optimal therapy.”

“We have seen such a broad array of rheumatic issues and questions with our patients,” Buchbinder said. “These effects can take so many different forms. They have led to limitations in treatment. We are learning how to treat patients safely, but we are still learning.”

Despite the challenges, Sharma is optimistic. “This is an incredible time in cancer therapy,” she said. “By involving the immune system and activating the immune system, we are unleashing a durable, long-term anti-tumor immune response. But even though these treatments come with these side effects, we are becoming more aware of them. As an oncologist, I believe that the benefits of these therapies outweigh the risks.” – by Rob Volansky

• References:
• Abdel-Wahab N, et al. Abstract #1342. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Calabrese C, et al. Abstract #1339. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Cappelli LC, et al. Arthritis Care Res (Hoboken). 2016;doi: 10.1002/acr.23177.
• Cappelli LC, et al. Ann Rheum Dis. 2017;doi:10.1136/annrheumdis-2016-209595.
• Cappelli L, et al. Abstract #1341. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Pinkston O, et al. Abstract #1340. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.

• For more information:
• Noha Abdel-Wahab, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Unit 1465, Houston, TX 77030; email: nahassan@mdanderson.org.
• Elizabeth I. Buchbinder, MD, can be reached at Dana-Farber Department of Communications, 20 Overland St., 3rd Floor Boston, MA 02215; email: johnw_noble@dfci.harvard.edu.
• Cassandra M. Calabrese, DO, can be reached at the Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: calabrc@ccf.org.
• Laura Cappelli, MD, MHS, can be reached at Johns Hopkins Arthritis Center, 5501 Hopkins Bayview Cir., Suite 1B1, Baltimore, MD 21224; email: lcappel1@jhmi.edu.
• Padmanee Sharma, MD, PhD, can be reached at the Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler St., Unit 1374, Houston, TX 77030; email: msimmons@mdanderson.org.

Disclosures: Abdel-Wahab, Calabrese and Cappelli report no relevant financial disclosures. Buchbinder reports she serves as a consultant for Checkmate Pharmaceuticals and that her group receives clinical trial funding from Amgen, Bristol-Myers Squibb, Checkmate, Eli Lilly, Merck and Novartis. Sharma reports she owns stock in Constellation, Evelo, Jounce, Kite Pharma and Neon and is a consult for Amgen, Astra Zeneca, Bristol-Myers Squibb, Constellation, EMD Serono, Evelo, GlaxoSmithKline, Jounce, Kite Pharma and Neon.