Sarthak Gupta, MD, on Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis

In the management of cancer, immune checkpoint inhibitors (ICIs) may cause immune system overactivation, leading to a novel entity of autoimmunity: immune-related adverse events. The most common musculoskeletal immune-related adverse event is ICI-induced inflammatory arthritis. Along with his colleagues, Sarthak Gupta, MD, completed a comprehensive review on ICI-induced inflammatory arthritis. In this podcast, Dr Gupta provides an overview of the diagnosis and management of the arthritis and why a multidisciplinary approach between rheumatologists and oncologists is key. 

Sarthak Gupta, MD, is an assistant research physician for the Lupus Clinical Trials Unit and the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Additional Resource:

Williams SG, Mollaeian A, Katz JD, Gupta S. Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management. Expert Rev Clin Immunol. 2020;16(8):771-785. doi:10.1080/1744666X.2020.1804362

TRANSCRIPT:

Colleen Murphy: Hello, everyone, and welcome to another installment of the Autoimmune Learning Network’s podcast series. I’m your moderator, Colleen Murphy, with the Autoimmune Learning Network. Today, I’m joined by Dr Sarthak Gupta.

Dr Gupta is an assistant research physician with the Lupus Clinical Trials Unit and the Systemic Autoimmunity Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. He’ll be talking with me today about a comprehensive review on immune checkpoint inhibitor-induced inflammatory arthritis that he and his team recently completed.

Thank you for joining me, Dr Gupta.

Sarthak Gupta: It’s a pleasure to be here, Colleen. And thank you for highlighting our work.

CM: Of course. Now, what you’ll be talking about is a newly recognized entity of autoimmunity. I'm excited for our audience to hear your insight. First, for some background, can you provide a brief overview of the connection between immune checkpoint inhibitors and immune-related adverse events?

SG: Sure. The introduction of immune checkpoint inhibitors, or ICIs, have really transformed the treatment paradigm for multiple cancers. ICIs have become a cornerstone in the management of many malignancies, including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, among others.

Their effectiveness and improvement in cancer survival rates derive from blocking surface ligands that are important in regulating responses to immunological stimuli. Blocking these proteins leads to T cell activation with consequent upregulation of the antitumor response.

However, along with the benefits of ICIs, their use has been associated with significant toxicities due to overactivation of the immune system and result in autoimmunity. This phenomena, frequently labeled immune-related adverse events or irAEs, presents a novel and challenging area in clinical management of oncology patients.

CM: Thank you for that background. I know you say immune checkpoint inhibitor-induced inflammatory arthritis is often under recognized. Why so, and what should clinicians be on the lookout for in their diagnostic evaluation?

SG: Our understanding of the prevalence of immune checkpoint inhibitor-induced inflammatory arthritis is limited to retrospective studies, which have reported a prevalence between 1.5% to 22%. That’s a wide range.

The exact incidence and prevalence of ICI-induced inflammatory arthritis are not well-understood due to the variability in presentation patterns as well as the differences in reporting and classification methodologies that are used between oncologists and rheumatologists. 

However, delays in diagnosis of inflammatory arthritis are not unique to oncology patients treated with ICI. We also see them in other forms of inflammatory arthritis. The reason for such delays include the fact that detection of inflammatory arthritis remains a challenge to nonspecialists.

We know that there is poor agreement between rheumatologists and primary care physicians in assessing sinusitis, and there is a lack of reliability in patients' health reporting of inflammatory signs. Lastly, also, there is a heterogeneity of ICI-induced inflammatory arthritis presentation.

Basically, clinicians should be cognizant of ICI-induced inflammatory arthritis, what it is, and recognize that patients on immune checkpoint inhibitors have a chance of developing inflammatory arthritis.

CM: Your review identified a few key differences that distinguish immune checkpoint inhibitor-induced inflammatory arthritis from other immune-related adverse events. What are those differences of which clinicians should be aware of?

SG: A distinguishing feature of many rheumatic immune-related adverse events is that their presentation is often delayed as compared with that of nondramatic irAEs, as we discussed above the multiple reasons that might happen.

Although dramatic immune-related adverse events have been reported as early as the same day of getting immune checkpoint inhibitor initiation. Some have been reported as late as 4 years after initiation. They may occur even after the checkpoint inhibitor itself has been discontinued.

Additionally, there’s been reports of active inflammation in ICI-induced inflammatory arthritis that may frequently persist despite cessation of checkpoint therapy. These are some unique features that distinguish the checkpoint-induced arthritis from other IRAs.

CM: I think that’s helpful for our listeners. What are some of the current optimal management strategies in immune checkpoint inhibitor-induced inflammatory arthritis that you identified in your review?

SG: The fundamental aspects of diagnosis and management of ICI-induced inflammatory arthritis include awareness, by way of high index of suspicion, and humility, by way of a broad differential diagnosis.

It’s important for an early referral to rheumatology, to establish the diagnosis, and then to help to manage musculoskeletal complaints in a way that enables the patient and oncologist to continue anticancer therapy.

Many patients appear to have a monophasic disease course and therefore a trial of nonsteroidal anti-inflammatory drugs, or NSAIDs, and/or corticosteroids has emerged as the first-line therapy. The corticosteroid dose necessary for symptom control, though, is highly variable.

We’ve seen some patients with severe arthritis that respond rapidly to 20 mg per day prednisone or its equivalent, while others fail to respond to high-dose corticosteroids and need additional therapy.

For those patients on whom symptoms of checkpoint-induced inflammatory arthritis are not adequately controlled or those who are unable to tolerate corticosteroid tapering without flaring up their arthritis or those who have a polycystic disease course, DMARDs, or disease-modifying antirheumatic drugs, have been successfully utilized, also.

Early initiation of DMARDs should also be considered in patients who have certain disease features that may confer high risk for treatment failure or for aggressive disease.

For example, those patients who have anti-CCP antibody positivity or show bone marrow edema or erosions on advanced imaging, like ultrasound or MRI, DMARDs, like methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, have been successfully used. Others have also shown benefit of using biological therapy, like a TNF inhibitor or an IL-6 inhibitor.

Lastly, the determination to hold or continue immune checkpoint inhibitor therapy, this can be very challenging. Unfortunately, there is little evidence to guide decision-making right now.

These factors that include severity of the arthritis and treatment response that are very important to take into account, and this has to be a shared decision-making between the patient, a rheumatologist, and oncologist, particularly in patients with moderate to severe inflammatory arthritis.

If the decision is made to hold checkpoint inhibitor therapy, it may be reasonable to resume therapy once the arthritis has improved or once arthritis has been controlled on a dose of 10 mg per day or less of prednisone or its equivalent.

CM: You touched a bit on my next question, which is, what is the importance of a multidisciplinary approach in the management of immune checkpoint inhibitor-induced inflammatory arthritis? You mentioned that rheumatologists and oncologist, in particular, should be working together.

Is there anyone else who should be included in that multidisciplinary approach? What should that collaboration look like?

SG: That’s a very important question, Colleen. Ultimately, the goal is to move towards uncoupling the beneficial antitumor response from the harmful immune-related toxicity, that is to say, maximizing the antitumor response while minimizing irAEs.

This will likely require continued collaboration of rheumatologists and oncologists in a multidisciplinary way, and it has to be patient-centered approach to manage the inflammatory arthritis.

It is critical that rheumatologists work with oncologists to identify risk factors for treatment refractory or aggressive inflammatory outsiders as well as to determine the true effect of antirheumatic therapies on the efficacy of checkpoint inhibitors in the setting of ICI-induced inflammatory arthritis.

For many patients, stopping or even holding the life-saving immunotherapy is a big decision. Our goal as physicians is to offer the best information that we have available to help them guide to make a decision that works best for them.

CM: You’ve shared a lot of great information here. In your review, you wrote that immune checkpoint inhibitor-induced inflammatory arthritis is a complex immune-related adverse event that you’re actually just beginning to understand mechanistically and pathologically. What knowledge gaps still exist in immune checkpoint inhibitor-induced inflammatory arthritis?

SG: That is true. We’re still in very early stages of understanding this entity, why some cancer patients get immune-related adverse events and that to why some patients get all of specific immune-related adverse events, maybe an effect of the kind of the checkpoint inhibitor itself as well as this complex interaction that we highlighted in our review between the patient, the tumor, and the environment.

We need further studies looking at tumor characteristics, host genetic factors, and the environmental factors important in modulating immune regulation and conferring risk for IRA. We need tissue-level information on the cell interactions that drive these processes, and these will be key to understand this entity.

Ideally, this will allow us to predict patients at high risk for irAEs, the type of immune-related adverse events that they may develop, and those who could benefit either from alternative therapies or from closer monitoring. We need to identify and validate markers that predict a chronic or aggressive course of irAE.

We need definitive answers to questions about whether steroids or DMARDs interfere with the antitumor response and which DMARDs are most efficacious in this setting.

As we learn more about immune checkpoint inhibitor-induced inflammatory arthritis, we expect to move toward early utilization of appropriate targeted DMARD therapy, which will hopefully allow us to identify therapies that both augment the tumor response and diminish off-target irAEs.

Lastly, I also think that irAEs present a unique opportunity to learn more about the underlying immunopathology of autoimmunity itself, as they may shed light on early and preclinical events in many rheumatologic conditions.

CM: This has all been very insightful. Dr Gupta, I want to thank you again for talking with me today and giving our listeners a look into your findings.

SG: I do appreciate you and ALN for highlighting our work. There’s so much still to learn, as I discussed, and, hopefully, we’ll have more answers soon.