Musculoskeletal Toxicities: Management of irAEs Guideline (Part 7)

An interview with Dr. Maria Suarez-Almazor from MD Anderson Cancer Center, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She reviews identification, evaluation & management of musculoskeletal toxicities in patients receiving ICPis, including inflammatory arthritis, myositis & polymyalgia-like syndrome in Part 7 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

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BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at ASCO.org/podcasts.

My name is Brittany Harvey, and today, we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Maria Suarez-Almazor from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And today, we're focusing on musculoskeletal toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Suarez-Almazor.

MARIA SUAREZ-ALMAZOR: Thank you.

BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for the guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Suarez-Almazor, do you have any relevant disclosures that are directly related to these guidelines?

MARIA SUAREZ-ALMAZOR: Thank you, Brittany. I don't have any disclosures directly related to the guidelines.

BRITTANY HARVEY: Thanks very much. Then getting into the content of this, what are the immune-related musculoskeletal toxicities addressed in this guideline?

MARIA SUAREZ-ALMAZOR: There are three major musculoskeletal syndromes covered in this guideline-- inflammatory arthritis, myositis, and polymyalgia rheumatica.

BRITTANY HARVEY: Great. Then let's start with that first one that you mentioned. So what are the key recommendations for identification, evaluation, and management of inflammatory arthritis?

MARIA SUAREZ-ALMAZOR: The diagnosis of inflammatory arthritis is primarily based on a thorough joint exam to detect the presence of synovitis and how many joints and what joints are actually involved. For this reason, we recommend early referral to a rheumatologist. From a diagnostic perspective, we recommend testing for antinuclear antibodies or ANA, rheumatoid factor, and cyclic citrullinated peptide antibodies or anti-CCP. These are only positive in 10% to 20% of patients but may be indicative of a more persistent disease.

As inflammatory arthritis does not have any specific biochemical parameters for follow up, we use inflammatory markers such as sed rate and CRP in conjunction with the clinical exam as indicators of disease activity. For grades 1 and 2, we recommend treatment with nonsteroidal anti-inflammatory drugs or NSAIDs, or low-dose steroids up to 20 milligrams of oral prednisone or equivalent. If there is involvement of only one or two joints, local treatment with steroid injections can be indicated.

For grade 3 and higher, the dose of steroids can be increased up to 0.5 to 1 milligram per kilogram of body weight. And if there is no improvement within two weeks or if the steroids cannot be satisfactorily tapered, we recommend early initiation of a disease-modifying antirheumatic drug or a DMARD, such as methotrexate, hydroxychloroquine, or sulfasalazine. We need to understand though that these may take up to two or three months to be effective.

Alternatively, we can use biologic agents which have a faster onset of action. Recommended agents include tumor necrosis factor or interleukin 6 receptor inhibitors. In severe cases, immune checkpoint inhibitors may need to be permanently discontinued. But the overall goal is to try to continue therapy while we treat the adverse event.

BRITTANY HARVEY: Understood. Appreciate your reviewing that information for inflammatory arthritis. Following that, what are the key recommendations for identification, evaluation, and management of myositis?

MARIA SUAREZ-ALMAZOR: Well, myositis is really the most serious of the musculoskeletal toxicities. And it can be life threatening, especially when it's associated with myocarditis and with myasthenia gravis features. It usually presents with proximal weakness of the upper and lower extremities and sometimes with myalgia and even rhabdomyolysis.

It usually is very acute in its presentation. Specific testing includes muscle enzymes, creatine kinase and aldolase, and electromyography and muscle biopsy if the diagnosis is uncertain. MRI can be useful as it can show muscle inflammation. And it can also assist in identifying a location for a biopsy if needed.

Consultation with rheumatology and neurology should be requested early on. We also recommend that all patients undergo testing of cardiac enzymes such as troponin. And if elevated, a cardiology consultation should be placed right away and further testing performed. For grades 1 and 2, if patient has symptoms, treatment with corticosteroids are 0.5 to 1 milligram per kilogram should be initiated.

For patients with grade 3 or 4, checkpoint inhibitors should be discontinued and the patient should be hospitalized. Corticosteroids should be initiated at a dose of 1 milligram per kilogram of prednisone or equivalent. And patients with severe compromise may need intravenous corticosteroid doses at higher doses of 1 or 2 milligrams per kilogram or even higher. For severe disease or if there is myocarditis or concomitant myasthenia gravis, we can consider plasmapheresis.

IVIG can also be used, but it has a slower onset of action. And it is important to remember that plasmapheresis can remove immunoglobulins. So if it is to be used, the IVIG should be administered after the plasmapheresis is completed. There are other immunosuppressant therapies such as biologic agents that can also be considered. And sometimes for maintenance, oral immunosuppressants such as azathioprine, methotrexate, or mycophenolate mofetil can also be considered. Patients with severe disease may need to permanently discontinue the checkpoint therapy.

BRITTANY HARVEY: OK, those details are helpful for clinicians. So then, for the last category, addressed in this guideline that you mentioned, what are the key recommendations for identification, evaluation, and management of polymyalgia-like syndrome.

MARIA SUAREZ-ALMAZOR: Polymyalgia rheumatica syndromes present with marked pain and stiffness of the muscles in the shoulder and hip girdles. But some patients can also present with concomitant inflammatory arthritis. The workup is very similar to that of arthritis. In these patients, it is very important though to obtain a creatine kinase so that the muscle enzyme to be certain that the myalgia is not from myositis, as a treatment would be very different. Although very rare, polymyalgia, in some instances can be associated with giant cell arteritis which, if present, would require more aggressive treatment. For this reason, it is important to ask the patient about symptoms such as headache, visual disturbances, or jaw claudication.

The management of polymyalgia-like immune adverse events alone, without any associated vasculitis, is very similar to that of arthritis. So we would use NSAIDs and low-dose steroids for grade 1 and 2. Higher doses of steroids and disease modifying agents, including biologics, might be needed for grades 3 and 4. But overall, very similar management as that of inflammatory arthritis.

BRITTANY HARVEY: Great. Thanks for reviewing all of those recommendations for those three different categories. So then, in your view, Dr. Suarez-Almazor, how will these recommendations for the management of musculoskeletal toxicities impact both clinicians and patients?

MARIA SUAREZ-ALMAZOR: Thank you, Brittany. For the most common rheumatologic adverse events, such as arthralgia, inflammatory arthritis, or polymyalgia-like syndromes, because they are not life threatening, we may not be as worried. But we need to recognize that they can greatly impair quality of life. So we really hope that these recommendations can assist patients and clinicians in the early recognition of symptoms and also in initiating prompt treatment so our goal to be able to continue checkpoint inhibitor therapy can be achieved by controlling the symptoms that really impair quality of life.

Myositis is a much more serious adverse event that can lead to death. Patients may not be able to restart immune checkpoint inhibitor therapy again after they develop myositis. So we hope that these recommendations do highlight the need for very prompt diagnosis, consultation with specialists, and very aggressive treatment early on to control and manage these devastating, life-threatening adverse event.

BRITTANY HARVEY: Definitely. Early recognition, treatment, and improved quality of life are key. So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Suarez-Almazor.

MARIA SUAREZ-ALMAZOR: Thank you, Brittany.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.ASCO.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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