What are the recommendations for using immune checkpoint inhibitors and Disease-Modifying Antirheumatic Drugs (DMARDs) together in patients with cancer and autoimmune disease?

Immune Checkpoint Inhibitors and DMARDs in Patients with Cancer and Autoimmune Disease

Pre-existing autoimmune disease should not prevent the use of immune checkpoint inhibitors, and DMARDs can be safely used to manage disease flares or immune-related adverse events that occur during cancer immunotherapy. 1

Pre-Treatment Baseline Management

Keep baseline immunosuppression at the lowest possible dose before starting checkpoint inhibitors—specifically, glucocorticoids should be below 10 mg prednisone equivalent per day if possible, as higher doses impair checkpoint inhibitor efficacy. 1, 2

• No preventive immunosuppressive treatment is needed before initiating checkpoint inhibitors 1
• Routine ANA screening before starting immunotherapy is not indicated, as baseline ANA does not predict immune-related adverse events in most cases 2
• For patients with thymoma specifically, test for anti-acetylcholine receptor and anti-striated muscle antibodies before starting checkpoint inhibitors 2

Expected Outcomes During Checkpoint Inhibitor Therapy

Approximately 47% of patients with pre-existing autoimmune disease will experience a flare of their underlying condition, and 43% will develop new immune-related adverse events, but less than 10% require checkpoint inhibitor discontinuation due to flares. 1, 2

• Disease flares occurred in 55% of rheumatoid arthritis patients (47/86), 50% of psoriatic arthritis patients (4/8), 64% of polymyalgia rheumatica patients (16/25), and 31% of spondyloarthritis patients (4/13) 1
• Only 8% of patients with pre-existing autoimmune disease discontinued checkpoint inhibitors due to immune-related adverse events unrelated to their baseline disease 1
• In a cohort of 112 patients, 79% continued checkpoint inhibitors despite flares or immune-related adverse events 1

DMARD Management Algorithm for Flares and Immune-Related Adverse Events

First-Line Treatment: Glucocorticoids

Start with glucocorticoids as first-line therapy for both disease flares and rheumatic immune-related adverse events, with dose and route determined by severity. 1

• For mild-moderate inflammatory arthritis: local or systemic glucocorticoids at appropriate doses 1
• For severe manifestations: 1-2 mg/kg/day prednisone (median 70 mg/day) 1
• Taper to the lowest effective dose once improvement is achieved 1

Second-Line Treatment: Conventional Synthetic DMARDs

Add conventional synthetic DMARDs (csDMARDs) when patients have insufficient response to acceptable glucocorticoid doses or require glucocorticoid-sparing therapy. 1

• Hydroxychloroquine, methotrexate, and sulfasalazine are the preferred csDMARDs, used as monotherapy or in combination 1
• Mycophenolate mofetil has been used successfully as second-line therapy 1
• Azathioprine can be considered but monitor for pancreatitis 1

Third-Line Treatment: Biologic DMARDs

For severe immune-related adverse events or insufficient response to csDMARDs, consider biologic DMARDs, with TNF or IL-6 inhibitors as preferred options for inflammatory arthritis. 1

• TNF inhibitors were primarily used for inflammatory bowel disease flares and new-onset colitis 1
• Infliximab had limited success (only 1 of 6 patients responded) 1
• Abatacept successfully resolved severe glucocorticoid-refractory myocarditis after plasma exchange failed 1

Special Considerations for Severe Manifestations

Checkpoint Inhibitor-Induced Myositis

Myositis requires immediate checkpoint inhibitor discontinuation if accompanied by dyspnea, bulbar symptoms (dysphagia, dysarthria, dysphonia), severe muscle weakness, or myocarditis. 1

• High-dose glucocorticoids (1-2 mg/kg/day) are mandatory first-line treatment 1
• Add intravenous immunoglobulins (used in 20% of reported cases) and/or plasma exchange (used in 10% of cases) for life-threatening manifestations 1
• Consider mycophenolate mofetil, methotrexate, or abatacept as rescue therapy in refractory situations 1
• Alemtuzumab has been used successfully in glucocorticoid-refractory myocarditis 1

Decision to Continue or Hold Checkpoint Inhibitors

Base the decision to continue or discontinue checkpoint inhibitors on the severity of rheumatic immune-related adverse events, extent of required immunosuppression, tumor response and duration, and future oncology treatment plans, in shared decision-making with the patient. 1

• Most flares and immune-related adverse events can be managed without checkpoint inhibitor discontinuation (79% of patients continued therapy) 1
• Only 21% of patients required permanent discontinuation due to immune-related adverse events 3
• Checkpoint inhibitor discontinuation is mandatory for life-threatening manifestations including myocarditis, severe respiratory failure, or severe bulbar symptoms 1

Common Pitfalls and Caveats

Avoid starting checkpoint inhibitors in patients on baseline immunosuppressive therapy exceeding 10 mg prednisone daily, as this is associated with shorter progression-free survival (3.8 months versus 12 months). 3

• Patients receiving immunosuppressive therapy at checkpoint inhibitor initiation had poorer cancer outcomes 3
• However, this data primarily reflects patients on steroids for cancer-related symptoms, not autoimmune disease management 1
• The decision requires multidisciplinary discussion between oncologist and rheumatologist, considering whether checkpoint inhibitors are used in metastatic versus adjuvant settings 1, 2